Method of preparation of heterocyclic molecules with pharmaceutical, pharmaceutical excipient, cosmeceutical, agrochemical and industrial uses

ABSTRACT

Processes for preparing racemic and optically pure 3,6-dihydro-2H-pyrans of formulae H, I, N and O are described. These compounds may be further transformed into compounds of formulae J, K, L, M, P, Q, S, T, U, V, Y and Z with potential pharmaceutical, pharmaceutical excipient, cosmeceutical, agrochemical and industrial applications.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 USC

371 National Stage application of PCT Application No. US2004/001344 filed Jan. 16, 2004; which claims the benefit under 35 USC

119(e) to U.S. application Ser. No. 60/440,982 filed Jan. 17, 2003, now abandoned. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.

BACKGROUND OF THE INVENTION

This invention pertains to processes that have utility in the construction of racemic and optically pure heterocyclic molecules that are to be screened for biological activities that would render them useful as pharmaceuticals, cosmeceuticals, pharmaceutical excipients or agrochemicals. More specifically, it pertains to the use of Ring-Closure olefin Metathesis (RCM) and Enzymatic Resolution (ER) for the production of optically pure synthetic intermediates during an organic synthesis and methods for elaboration of same.

BACKGROUND INFORMATION

Carbohydrates or saccharides are highly functionalized biomolecules present in plant and animal cells and tissues. These molecules play a key role in energy storage, cellular signaling and molecular recognition. Carbohydrates are critical in the early stages of inflammation and immune response and contribute to the progression of a number of diseases. In general, saccharides are poor therapeutic agents. These compounds are rapidly metabolized in the gut or the plasma and have low binding affinities to their targets. In addition, carbohydrates are difficult to synthesize and purify by conventional methods. The combination of the above drawbacks has considerably limited the use of saccharides as pharmaceuticals, cosmeceuticals, pharmaceutical excipients or agrochemicals. Such difficulties maybe overcome by the use of “carbohydrate mimetics” or optically active heterocyclic molecules that resemble, carbohydrates but have improved stability, target affinity and synthetic availability.

One strategy for increasing the stability of carbohydrate mimetics is to replace the heteroatom anomeric linkage of the carbohydrate ring system with a non-heteroatom linkage. Traditionally, these carbohydrate mimetics have been prepared by direct cleavage of the anomeric carbon-oxygen bond with a hydride equivalent, as set forth in Rolf, D. et al J. Amer. Chem. Soc. 1982, 104, 3539-3541. Such transformations are commonly carried out by reaction of the alkyl or acyl glycoside with a strong Lewis acid such as boron trifluoride etherate (BF₃.Et₂O), trifluoroacetic acid (CF₃CO₂H) and/or trimethylsilyl trifluoromethanesulfonate (TMSOSO₂CF₃) in the presence of an ionic hydride donor such as a trialkylsilane (FIG. 1). Said carbohydrate mimetics have also been prepared by direct cleavage of the anomeric carbon-oxygen bond with a cyanide equivalent, as set forth in Martin, J. et al Tetrahedron Lett. 1998, 39, 5927-5930. Such transformations are commonly carried out by reaction of the bromoglycoside with a free radical initiator (e.g. AIBN) in the presence of an alkyl isocyanide (FIG. 1). The use of trialkylsilyl cyanides for the preparation of cyano glycosides has also been described as set forth in Igarashi, Y. et al Bioorg. Med. Chem. Lett. 1997, 7(5), 613-616.

Such methodologies ultimately depend on the availability of the glycoside and are thereby limited in scope. Another drawback of the existing art is that the cleavage of the anomeric carbon-oxygen bond is not stereospecific and usually yields a mixture of stereoisomers. As such, there is an obvious and immediate need for novel methodology that provides rapid access to large quantities of optically pure heterocyclic molecules such as those set forth in this invention.

BRIEF DESCRIPTION OF THE INVENTION

Prior art preparations of carbohydrate mimetics are shown in FIG. 1.

The optically pure carbohydrate mimetics of the instant invention are shown in FIG. 2.

Schemes 1 to 10 on sheets 2 to 11 illustrate the chemical reactions used in making the optically pure carbohydrate mimetics of the invention.

SUMMARY OF THE INVENTION

Relative to traditional methods, efficiency is introduced into the syntheses of these carbohydrate mimetics by combining starting materials according to formulae A and D, or formulae B and E, to provide esters according to formula C. Compounds according to formula C can then react with aldehydes according to formula F to provide acyclic intermediates according to formula G. Application of a stereoselective Ring Closure olefin Metathesis (RCM) reaction to compounds according to formula G provides the 3,6-dihydro-2H-pyrans according to formulae H or I. These intermediates are subsequently transformed into optically pure stereoisomers via enzymatic resolution (Scheme 1). It is to be understood that the transformation of compounds according to formula G to optically pure compounds according to formulae H or I can also be carried out by way of an enantioselective Ring Closure olefin Metathesis (RCM) reaction.

Efficiency is also introduced into the syntheses of these carbohydrate mimetics by reduction of compounds according to formula G to compounds according to formula W. Subsequent reaction of compounds according to formula W with carbonyl compounds according to formula R provides acyclic intermediates according to formula X. Application of a stereoselective Ring Closure olefin Metathesis (RCM) reaction to compounds according to formula X provides the 3,6-dihydro-2H-pyrans according to formula S (Scheme 2). It is to be understood that the transformation of compounds according to formula X to optically pure compounds according to formula S can also be carried out by way of an enantioselective Ring Closure olefin Metathesis (RCM) reaction. When subjected to other synthetic transformations, compounds according to formula H, I and S provide a variety optically pure carbohydrate mimetics according to formulae J, K, L, M, N, O, P, Q, T, U, V, Y and Z (FIG. 2).

One advantage of this method over existing state of the art is that it provides rapid access to large quantities of optically pure compounds according to formulae H, I, J, K, L, M, N, O, P, Q, S, T, U, V, Y and Z. Another advantage of this method is that it allows the introduction of a variety of substituents into compounds according to formulae H, I, J, K, L, M, N, O, P, Q, S, T, U, V, Y and Z.

In one aspect of this invention, said carbohydrate mimetics can be used to generate molecules or diverse compound libraries with potential pharmaceutical, pharmaceutical excipient, cosmeceutical, agrochemical or industrial applications.

In another aspect of this invention, said carbohydrate mimetics can be linked to polymeric supports and/or other molecules in order to generate diverse compound libraries with potential pharmaceutical, pharmaceutical excipient, cosmeceutical, agrochemical or industrial applications.

In still another aspect of this invention, said carbohydrate mimetics can be coordinated to metals in order to generate organometallic complexes or catalysts with potential pharmaceutical, pharmaceutical excipient, cosmeceutical, agrochemical or industrial applications as set forth in Kanai, M. et al Tetrahedron Lett. 2000, 41, 2405-2409; Groaning, M. D. et al Tetrahedron Lett. 1998, 39, 5485-5488; Bell, D. et al U.S. Pat. No. 5,916,975 Jun. 29, 1999; and RajanBabu, T. V. et al J. Org. Chem. 1997, 62, 6012-6028.

Accordingly, the present invention describes a process shown in scheme 3 for preparing pharmaceuticals, pharmaceutical excipients, cosmeceuticals or agrochemicals comprising:

-   -   1. An allylic halide reagent A is first reacted with an         α-hydroxycarboxylic ester D forming an oxygen-carbon bond and         forming ether C; alternatively, an allylic alcohol reagent B is         first reacted with an α-substituted ester D forming an         oxygen-carbon bond and forming ether C.     -   2. The resulting compound according to formula C is reacted in a         subsequent synthetic step with an α,β-unsaturated carbonyl         compound according to formula F forming a carbon-carbon bond and         forming a compound according to formula G;     -   3. The resulting compound according to formula G is reacted with         a ring-closing olefin metathesis (RCM) catalyst forming a         carbon-carbon bond and forming substituted 3,6-dihydro-2H-pyrans         according to formulae H or I.     -   4. The resulting compound according to formulae H or I is         reacted with an enzyme producing the optically pure substituted         3,6-dihydro-2H-pyrans according to formulae H or I.     -   5. The resulting compound according to formulae H or I is         reacted with an oxidant forming substituted tetrahydropyran         according to formula J.     -   6. The resulting compound according to formula J is reacted with         an enzyme or an electrophilic reagent producing the compound         according to formula K.     -   7. The resulting compound according to formula K or         alternatively the compound according to formula J is reacted         under microwave radiation forming substituted         bicyclo[3.2.1]lactone according to formula L.     -   8. The resulting compound according to formula L is reacted with         a nucleophilic reagent forming substituted tetrahydropyran         according to formula M.

It is to be understood that the process shown in scheme 3 applies to all stereoisomers of compounds G, H, I, J, K, L and M.

Accordingly, the present invention also describes a process shown in scheme 4 for preparing pharmaceuticals, pharmaceutical excipients, cosmeceuticals or agrochemicals comprising:

-   -   1. An allylic halide reagent A is first reacted with an         α-hydroxycarboxylic ester D forming an oxygen-carbon bond and         forming ether C; alternatively, an allylic alcohol reagent B is         first reacted with an α-substituted ester D forming an         oxygen-carbon bond and forming ether C.     -   2. The resulting compound according to formula C is reacted in a         subsequent synthetic step with an α,β-unsaturated carbonyl         compound according to formula F forming a carbon-carbon bond and         forming a compound according to formula G;     -   3. The resulting compound according to formula G is reacted with         a ring-closing olefin metathesis (RCM) catalyst forming a         carbon-carbon bond and forming substituted 3,6-dihydro-2H-pyrans         according to formulae H or I.     -   4. The resulting compound according to formulae H or I is         reacted with an enzyme producing the optically pure substituted         3,6-dihydro-2H-pyrans according to formulae H or I.     -   5. The resulting compound according to formulae H or I is         reacted with a reducing reagent forming substituted         3,6-dihydro-2H-pyran according to formula N.     -   6. The resulting compound according to formula N is reacted with         an electrophilic reagent forming substituted         2,6-dihydro-2H-pyran according to formula O.     -   7. The resulting compound according to formula 0 is reacted with         an epoxidation reagent forming substituted         3,7-dioxabicyclo[4.1.0]heptane according to formula P.     -   8. The resulting compound according to formula P is reacted with         a nucleophilic reagent forming substituted tetrahydropyran         according to formula Q.

It is to be understood that the process shown in scheme 4 applies to all stereoisomers of compounds G, H, I, N, O, P and Q.

Accordingly, the present invention also describes a process shown in scheme 5 for preparing pharmaceuticals, pharmaceutical excipients, cosmeceuticals or agrochemicals comprising:

-   -   1. An allylic halide reagent A is first reacted with an         α-hydroxycarboxylic ester D forming an oxygen-carbon bond and         forming ether C; alternatively, an allylic alcohol reagent B is         first reacted with an α-substituted ester D forming an         oxygen-carbon bond and forming ether C.     -   2. The resulting compound according to formula C is reacted in a         subsequent synthetic step with an α,β-unsaturated carbonyl         compound according to formula F forming a carbon-carbon bond and         forming a compound according to formula G;     -   3. The resulting compound according to formula G is reacted with         a ring-closing olefin metathesis (RCM) catalyst forming a         carbon-carbon bond and forming substituted 3,6-dihydro-2H-pyrans         according to formulae H or I.     -   4. The resulting compound according to formulae H or I is         reacted with a reducing reagent forming substituted         3,6-dihydro-2H-pyran according to formula N.     -   5. The resulting compound according to formula N is reacted with         an electrophilic reagent forming substituted         2,6-dihydro-2H-pyran according to formula O.     -   6. The resulting compound according to formula O is reacted with         an epoxidation reagent forming substituted         3,7-dioxabicyclo[4.1.0]heptane according to formulae P or Y.     -   7. The resulting compound according to formulae P or Y is         reacted with an enzyme producing the optically pure substituted         3,7-dioxabicyclo[4.1.0]heptane according to formula P.     -   8. Alternatively, the compound according to formula N is reacted         with an epoxidation reagent forming substituted         3,7-dioxabicyclo[4.1.0]heptane according to formula Z.     -   9. The resulting compound according to formula Z is reacted with         an enzyme producing the optically pure substituted         3,7-dioxabicyclo[4.1.0]heptane according to formula P.     -   10. The resulting compound according to formula P is reacted         with a nucleophilic reagent forming substituted tetrahydropyran         according to formula Q.

It is to be understood that the process shown in scheme 5 applies to all stereoisomers of compounds G, H, I, N, O, P, Q, Y and Z.

Accordingly, the present invention also describes a process shown in scheme 6 for preparing pharmaceuticals, pharmaceutical excipients, cosmeceuticals or agrochemicals comprising:

-   -   1. An allylic halide reagent A is first reacted with an         α-hydroxycarboxylic ester D forming an oxygen-carbon bond and         forming ether C; alternatively, an allylic alcohol reagent B is         first reacted with an α-substituted ester D forming an         oxygen-carbon bond and forming ether C.     -   2. The resulting compound according to formula C is reacted in a         subsequent synthetic step with an α,β-unsaturated carbonyl         compound according to formula F forming a carbon-carbon bond and         forming a compound according to formula G;     -   3. The resulting compound according to formula G is reacted with         a ring-closing olefin metathesis (RCM) catalyst forming a         carbon-carbon bond and forming substituted 3,6-dihydro-2H-pyrans         according to formulae H or I.     -   4. The resulting compound according to formulae H or I is         reacted with a reducing reagent forming substituted         3,6-dihydro-2H-pyran according to formula N.     -   5. The resulting compound according to formula N is reacted with         an electrophilic reagent forming substituted         2,6-dihydro-2H-pyran according to formula O.     -   6. The resulting compound according to formula O is reacted with         an epoxidation reagent forming the optically pure substituted         3,7-dioxabicyclo[4.1.0]heptane according to formulae P, Y or Z.     -   7. The resulting compound according to formulae P, Y or Z is         reacted with a nucleophilic reagent forming substituted         tetrahydropyran according to formula Q.

It is to be understood that the process shown in scheme 6 applies to all stereoisomers of compounds G, H, I, N, O, P, Q, Y and Z.

Accordingly, the present invention also describes a process shown in scheme 7 for preparing pharmaceuticals, pharmaceutical excipients, cosmeceuticals or agrochemicals comprising:

-   -   1. An allylic halide reagent A is first reacted with an         α-hydroxycarboxylic ester D forming an oxygen-carbon bond and         forming ether C; alternatively, an allylic alcohol reagent B is         first reacted with an α-substituted ester D forming an         oxygen-carbon bond and forming ether C.     -   2. The resulting compound according to formula C is reacted in a         subsequent synthetic step with an α,β-unsaturated carbonyl         compound according to formula F forming a carbon-carbon bond and         forming a compound according to formula G;     -   3. The resulting compound according to formula G is reacted with         a ring-closing olefin metathesis (RCM) catalyst forming a         carbon-carbon bond and forming substituted 3,6-dihydro-2H-pyrans         according to formulae H or I.     -   4. The resulting compound according to formulae H or I is         reacted with an enzyme producing the optically pure substituted         3,6-dihydro-2H-pyrans according to formulae H or I.     -   5. The resulting compound according to formulae H or I is         reacted with a reducing reagent forming substituted         3,6-dihydro-2H-pyran according to formula N.     -   6. The resulting compound according to formula N is reacted with         a carbonyl compound according to formula R forming substituted         tetrahydropyran according to formula S.     -   7. The resulting compound according to formula S is reacted with         an epoxidation reagent forming substituted         hexahydro-1,3,5,7-tetraoxacyclopropa[a]naphthalene according to         formula T.     -   8. The resulting compound according to formula T is reacted with         a nucleophilic reagent forming substituted tetrahydropyran         according to formula U.

It is to be understood that the process shown in scheme 7 applies to all stereoisomers of compounds G, H, I, N, S, T and U.

Accordingly, the present invention also describes a process shown in scheme 8 for preparing pharmaceuticals, pharmaceutical excipients, cosmeceuticals or agrochemicals comprising:

-   -   1. An allylic halide reagent A is first reacted with an         α-hydroxycarboxylic ester D forming an oxygen-carbon bond and         forming ether C; alternatively, an allylic alcohol reagent B is         first reacted with an α-substituted ester D forming an         oxygen-carbon bond and forming ether C.     -   2. The resulting compound according to formula C is reacted in a         subsequent synthetic step with an α,β-unsaturated carbonyl         compound according to formula F forming a carbon-carbon bond and         forming a compound according to formula G;     -   3. The resulting compound according to formula G is reacted with         a ring-closing olefin metathesis (RCM) catalyst forming a         carbon-carbon bond and forming substituted 3,6-dihydro-2H-pyrans         according to formulae H or I.     -   4. The resulting compound according to formulae H or I is         reacted with an enzyme producing the optically pure substituted         3,6-dihydro-2H-pyrans according to formulae H or I.     -   5. The resulting compound according to formulae H or I is         reacted with a reducing reagent forming substituted         3,6-dihydro-2H-pyran according to formula N.     -   6. The resulting compound according to formula N is reacted with         a carbonyl compound according to formula R forming substituted         tetrahydropyran according to formula S.     -   7. The resulting compound according to formula S is reacted with         an oxidant forming substituted tetrahydropyran according to         formula V.

It is to be understood that the process shown in scheme 8 applies to all stereoisomers of compounds G, H, I, N, S and V.

Accordingly, the present invention also describes a process shown in scheme 9 for preparing pharmaceuticals, pharmaceutical excipients, cosmeceuticals or agrochemicals comprising:

-   -   1. An allylic halide reagent A is first reacted with an         α-hydroxycarboxylic ester D forming an oxygen-carbon bond and         forming ether C; alternatively, an allylic alcohol reagent B is         first reacted with an α-substituted ester D forming an         oxygen-carbon bond and forming ether C.     -   2. The resulting compound according to formula C is reacted in a         subsequent synthetic step with an α,β-unsaturated carbonyl         compound according to formula F forming a carbon-carbon bond and         forming a compound according to formula G;     -   3. The resulting compound according to formula G is reacted with         a ring-closing olefin metathesis (RCM) catalyst forming a         carbon-carbon bond and forming substituted 3,6-dihydro-2H-pyrans         according to formulae H or I.     -   4. The resulting compound according to formulae H or I is         reacted with a reducing reagent forming substituted         3,6-dihydro-2H-pyran according to formula N.     -   5. The resulting compound according to formula N is reacted with         a carbonyl compound according to formula R forming substituted         tetrahydropyran according to formula S.     -   6. The resulting compound according to formula S is reacted with         an oxidant forming optically pure substituted tetrahydropyran         according to formula V.

It is to be understood that the process shown in scheme 8 applies to all stereoisomers of compounds G, H, I, N, S and V.

Accordingly, the present invention also describes a process shown in scheme 10 for preparing pharmaceuticals, pharmaceutical excipients, cosmeceuticals or agrochemicals comprising:

-   -   1. An allylic halide reagent A is first reacted with an         α-hydroxycarboxylic ester D forming an oxygen-carbon bond and         forming ether C; alternatively, an allylic alcohol reagent B is         first reacted with an α-substituted ester D forming an         oxygen-carbon bond and forming ether C.     -   2. The resulting compound according to formula C is reacted in a         subsequent synthetic step with an α,β-unsaturated carbonyl         compound according to formula F forming a carbon-carbon bond and         forming a compound according to formula G;     -   3. The resulting compound according to formula G is reacted with         a reducing reagent forming an alcohol according to formula W.     -   4. The resulting compound according to formula W is reacted with         a carbonyl compound according to formula R forming a compound         according to formula X.     -   5. The resulting compound according to formula X is reacted with         a ring-closing olefin metathesis (RCM) catalyst forming a         carbon-carbon bond and forming substituted tetrahydropyrans         according to formula S.     -   6. The resulting compound according to formula S is then reacted         according to schemes 7, 8 or 9 forming optically pure         substituted tetrahydropyrans according to formula T, U and V.

It is to be understood that the process shown in scheme 8 applies to all stereoisomers of compounds G, W, X, and S.

Accordingly, the present invention also describes processes for preparing pharmaceuticals, pharmaceutical excipients, cosmeceuticals or agrochemicals comprising:

-   -   1. Compounds according to formulae H, I, J, K, L, M, N, O, P, Q,         S, T, U, V, Y and Z can be linked to polymeric supports and/or         other molecules in order to generate diverse compound libraries         with potential pharmaceutical, pharmaceutical excipient,         cosmeceutical, or agrochemical use.     -   2. Compounds according to formulae H, I, J, K, L, M, N, O, P, Q,         S, T, U, V, Y and Z can be linked to metals and/or other metal         containing molecules in order to generate diverse compound         libraries with potential pharmaceutical, pharmaceutical         excipient, cosmeceutical, or agrochemical use.     -   3. Compounds according to formulae H, I, J, K, L, M, N, O, P, Q,         S, T, U, V, Y and Z can be linked to metals and/or other metal         containing molecules and thereby serve as chiral catalysts in         order to generate diverse compound libraries with potential         pharmaceutical, pharmaceutical excipient, cosmeceutical, or         agrochemical use.     -   4. Compounds according to formulae H, I, J, K, L, M, N, O, P, Q,         S, T, U, V, Y and Z can be linked to achiral reagents and         thereby serve as chiral auxiliaries in order to generate diverse         compound libraries with potential pharmaceutical, pharmaceutical         excipient, cosmeceutical, or agrochemical use.     -   5. Compounds according to formulae H, I, J, K, L, M, N, O, P, Q,         S, T, U, V, Y and Z can be linked to other molecules and thereby         serve as solubilizing agents in order to generate diverse         compound libraries with potential pharmaceutical, pharmaceutical         excipient, cosmeceutical, or agrochemical use.     -   6. Compounds according to formulae H, I, J, K, L, M, N, O. P, Q,         S, T, U, V, Y and Z can be, linked to other molecules in order         to generate diverse compound libraries of prodrugs with         potential pharmaceutical, pharmaceutical excipient,         cosmeceutical, or agrochemical use.

DEFINITIONS

The compounds according to this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The term “stereoisomer” refers to a chemical compound having the same molecular weight, chemical composition, and constitution as another, but with the atoms grouped differently. That is, certain identical chemical moieties are at different orientations in space and, therefore, when pure, have the ability to rotate the plane of polarized light. However, some pure stereoisomers may have an optical rotation that is so slight that it is undetectable with present instrumentation. The compounds described herein may have one or more asymmetrical carbon atoms and therefore include various stereoisomers. All such isomeric forms of these compounds are expressly included in the present invention.

Each stereogenic carbon may be of R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned. When chiral centers are found in the derivatives of this invention, it is to be understood that this invention encompasses all possible stereoisomers. For example, in compounds according to formula H, the carbon atoms to which —OR₉ and —CO₂R₁ are attached may have an R,R or S,S or S,R or R,S configuration. Similarly, in formula Q, the carbon atoms to which R₂, R₅, R₁₄, —OR₉ and —CH₂OR₁₃ are attached may have an R,R,R,R or S,S,S,S or S,R,R,R or R,S,S,S or R,S,R,R or S,R,S,S or R,R,S,R or S,S,R,S or R,R,R,S or S,S,S,R or S,S,R,R or R,R,S,S or S,R,S,R or R,S,R,S or S,R,R,S or R,S,S,R configuration.

The terms “optically pure compound” or “optically pure isomer” refers to a single stereoisomer of a chiral compound regardless of the configuration of the said compound.

For purpose of this application, all sugars are referenced using conventional three-letter nomenclature. All sugars are assumed to be in the D-form unless otherwise noted, except for fucose, which is in the L-form. Further, all sugars are in the pyranose form.

The following examples of nomenclature, numbering systems and stereochemical assignments are provided for reference.

The term “substantially homogeneous” refers to collections of molecules wherein at least 80%, preferably at least about 90% and more preferably at least about 95% of the molecules are a single compound or a single stereoisomer thereof.

As used herein, the term “attached” signifies a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art.

The term “Lewis acid” refers to a molecule that can accept an unshared pair of electrons and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of “Lewis acid” includes but is not limited to: boron trifluoride, boron trifluoride etherate, boron trifluoride tetrahydrofuran complex, boron trifluoride tert-butyl-methyl ether complex, boron trifluoride dibutyl ether complex, boron trifluoride dihydrate, boron trifluoride di-acetic acid complex, boron trifluoride dimethyl sulfide complex, boron trichloride, boron trichloride dimethyl sulfide complex, boron tribromide, boron tribromide dimethyl sulfide complex, boron triiodide, triimethoxyborane, triethoxyborane, trimethylaluminum, triethylaluminum, aluminum trichloride, aluminum trichloride tetrahydrofuran complex, aluminum tribromide, titanium tetrachloride, titanium tetrabromide, titanium iodide, titanium tetraethoxide, titanium tetraisopropoxide, scandium (III) trifluoromethanesulfonate, yttrium (III) trifluoromethanesulfonate, ytterbium (III) trifluoromethanesulfonate, lanthanum (III) trifluoromethanesulfonate, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, zinc (II) trifluoromethanesulfonate, zinc (II) sulfate, magnesium sulfate, lithium perchlorate, copper (II) trifluoromethanesulfonate, copper (II) tetrafluoroborate and the like. Certain Lewis acids may have optically pure ligands attached to the electron acceptor atom, as set forth in Corey, E. J. Angewandte Chemie, International Edition (2002), 41(10), 1650-1667; Aspinall, H. C. Chemical Reviews (Washington, D.C., United States) (2002), 102(6), 1807-1850; Groger, H. Chemistry—A European Journal (2001), 7(24), 5246-5251; Davies, H. M. L. Chemtracts (2001), 14(11), 642-645; Wan, Y. Chemtracts (2001), 14(11), 610-615; Kim, Y. H. Accounts of Chemical Research (2001), 34(12), 955-962; Seebach, D. Angewandte Chemie, International Edition (2001), 40(1), 92-138; Blaser, H. U. Applied Catalysis, A: General (2001), 221(1-2), 119-143; Yet, L. Angewandte Chemie, International Edition (2001), 40(5), 875-877; Jorgensen, K. A. Angewandte Chemie, International Edition (2000), 39(20), 3558-3588; Dias, L. C. Current Organic Chemistry (2000), 4(3), 305-342; Spindler, F. Enantiomer (1999), 4(6), 557-568; Fodor, K. Enantiomer (1999), 4(6), 497-511; Shimizu, K. D.; Comprehensive Asymmetric Catalysis I-III (1999), 3, 1389-1399; Kagan, H. B. Comprehensive Asymmetric Catalysis I-III (1999), 1, 9-30; Mikami, K. Lewis Acid Reagents (1999), 93-136 and all references cited therein. Such Lewis acids maybe used by one of ordinary skill and knowledge in the art to produce optically pure compounds from achiral starting materials.

The term “acylating agent” refers to a molecule that can transfer an alkylcarbonyl, substituted alkylcarbonyl or aryl carbonyl group to another molecule. The definition of “acylating agent” includes but is not limited to ethyl acetate, vinyl acetate, vinyl propionate, vinyl butyrate, isopropenyl acetate, 1-ethoxyvinyl acetate, trichloroethyl butyrate, trifluoroethyl butyrate, trifluoroethyl laureate, S-ethyl thiooctanoate, biacetyl monooxime acetate, acetic anhydride, succinic anhydride, diketene, diallyl carbonate, carbonic acid but-3-enyl ester cyanomethyl ester, amino acid and the like.

The term “nucleophile” or “nucleophilic reagent” refers to a negatively charged or neutral molecule that has an unshared pair of electrons and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of “nucleophile” includes but is not limited to: water, alkylhydroxy, alkoxy anion, arylhydroxy, aryloxy anion, alkylthiol, alkylthio anion, arylthiol, arylthio anion, ammonia, alkylamine, arylamine, alkylamine anion, arylamine anion, hydrazine, alkyl hydrazine, arylhydrazine, alkylcarbonyl hydrazine, arylcarbonyl hydrazine, hydrazine anion, alkyl hydrazine anion, arylhydrazine anion, alkylcarbonyl hydrazine anion, arylcarbonyl hydrazine anion, cyanide, azide, hydride, alkyl anion, aryl anion and the like.

The term “electrophile” or “electrophilic reagent” refers to a positively charged or neutral molecule that has an open valence shell and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of “electrophile” includes but is not limited to: hydronium, acylium, lewis acids, such as for example, boron trifluoride and the like, halogens, such as for example Br₂ and the like, carbocations, such as for example tert-butyl cation and the like, diazomethane, trimethylsilyidiazomethane, alkyl halides, such as for example methyl iodide, benzyl bromide and the like, alkyl triflates, such as for example methyl triflate and the like, alkyl sulfonates, such as for example ethyl toluenesulfonate, butyl methanesulfonate and the like, acyl halides, such as for example acetyl chloride, benzoyl bromide and the like, acid anhydrides, such as for example acetic anhydride, succininc anhydride, maleic anhydride and the like, isocyanates, such as for example methyl isocyanate, phenylisocyanate and the like, chloroformates, such as for example methyl chloroformate, ethyl chloroformate, benzyl chloroformate and the like, sulfonyl halides, such as for example methanesulfonyl chloride, p-tolunesulfonyl chloride and the like, silyl halides, such as for example trimethylsilyl chloride, tertbutyldimethyl silyll chloride and the like, phosphoryl halide such as for example dimethyl chlorophosphate and the like, alpha-beta-unsaturated carbonyl compounds such as for example acrolein, methyl vinyl ketone, cinnamaldehyde and the like.

The term “oxidant” refers to any reagent that will increase the oxidation state of a carbon atom in the starting material by either adding an oxygen atom to this carbon or removing an electron from this carbon and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of “oxidant” includes but is not limited to: osmium tetroxide, ruthenium tetroxide, ruthenium trichloride, potassium permanganate, meta-chloroperbenzoic acid, hydrogen peroxide, dimethyl dioxirane and the like.

The term “metal ligand” refers to a molecule that has an unshared pair of electrons and can coordinate to a metal atom and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of “metal ligand” includes but is not limited to: water, alkoxy anion, alkylthio anion, ammonia, trialkylamine, triarylamine, trialkylphosphine, triarylphosphine, cyanide, azide and the like.

The term “epoxidation reagent” refers to any reagent that will transform an alkene into an epoxide. The definition of “epoxidation reagent” includes but is not limited to: oxygen, tert-butyl hydroperoxide, meta-chloroperbenzoic acid, dimethyl dioxirane, oxone, sodium hypochlorite, sodium periodate, iodosylbenzene and the like. Certain transition metals and ligands facilitate the epoxidation of alkenes. Examples of such transition metal reagents include: titanium tetraisopropoxide, polymer supported cyclopentadienyl titanium trichloride, zirconium tetraethoxide, hafnium tetraisopropoxide, vanadium pentoxide, niobium pentaethoxide, tantalum pentaisopropoxide, manganese (II) trifluoromethanesulfonate, iron (III) acetylacetonate, molybdenum hexacarbonyl, ruthenium dichloride tris(triphenylphosphine), cobalt (II) trifluoromethanesulfonate, and the like. Examples of such ligands include: (R,R) diethyl tartarate, (S,S) diethyl tartarate, N-ethyl ephedrine, N-methylprolinol, porphyrin, 2,2′-[[(1S,2S)-1,2-diphenyl-1,2-ethanediyl]-bis(nitrilomethylidyne)]bis[6-(1,1-dimethylethyl)-4-methyl-phenol, 2,2′-[[(1R,2R)-1,2-diphenyl-1,2-ethanediyl]-bis(nitrilomethylidyne)]bis[6-(1,1-dimethylethyl)-4-methyl-phenol, 2,2′-[(1R,2R)-1,2-cyclohexanediylbis[(E)-nitrilomethylidyne]]bis[6-(1,1-dimethylethyl)-4-methyl-phenol and the like. Such chiral ligands maybe used by one of ordinary skill and knowledge in the art to produce optically pure epoxides from alkene starting materials.

The term “reducing reagent” refers to any reagent that will decrease the oxidation state of a carbon atom in the starting material by either adding a hydrogen atom to this carbon or adding an electron to this carbon and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of “reducing reagent” includes but is not limited to: borane-dimethyl sulfide complex, 9-borabicyclo[3.3.1.]nonane (9-BBN), catechol borane, lithium borohydride, sodium borohydride, sodium borohydride-methanol complex, potassium borohydride, sodium hydroxyborohydride, lithium triethylborohydride, lithium n-butylborohydride, sodium cyanoborohydride, calcium (II) borohydride, lithium aluminum hydride, diisobutylaluminum hydride, n-butyl-diisobutylaluminum hydride, sodium bis-methoxyethoxyaluminum hydride, triethoxysilane, diethoxymethylsilane, lithium hydride, lithium, sodium, hydrogen Ni/B, and the like. Certain acidic and Lewis acidic reagents enhance the activity of reducing reagents. Examples of such acidic reagents include: acetic acid, methanesulfonic acid, hydrochloric acid, and the like. Examples of such Lewis acidic reagents include: trimethoxyborane, triethoxyborane, aluminum trichloride, lithium chloride, vanadium trichloride, dicyclopentadienyl titanium dichloride, cesium fluoride, potassium fluoride, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, and the like.

The term “coupling reagent” refers to any reagent that will activate the carbonyl of a carboxylic acid and facilitate the formation of an ester or amide bond. The definition of “coupling reagent” includes but is not limited to: acetyl chloride, ethyl chloroformate, dicyclohexylcarbodiimide (DCC), diisopropyl carbodiiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl), N-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 4-nitrophenol, pentafluorophenol, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), O-benzotriazole-N,N,N′N′-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate, bromo-trispyrrolidino-phosphonium hexafluorophosphate, 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), tetramethylfluoroformamidinium hexafluorophosphate and the like.

The terms “resin”, “resin bound”, “polymeric resin”, “polymeric resin support”, “polymeric support” or “solid support” refer to, at all occurrences, a bead or other solid support, which would be obvious to one of ordinary skill and knowledge in the art. The preferred polymer resins for use herein are the Merrifield, hydroxymethyl, aminomethyl, benzhydrylamine, 4-methylbenhydrylamine, Wang and Rink resins and the like (available commercially from Advanced Chemtech, Chemimpex and the like). Other solid supports that are suitably substituted and made of a cross-linked polystyrene resin or polyethylene glycol-polystyrene resin can also be used. Additionally, a “linker”, defined here as any aliphatic or aromatic reagent that tethers a given organic or organometallic compound to the solid-support and which lacks functionality that will participate in any synthetic chemistry subsequently carried out on the solid-support, can be used.

The term “removable protecting group” or “protecting group” refers to any group which when bound to a functionality, such as the oxygen atom of a hydroxyl or carboxyl group or the nitrogen atom of an amino group, prevents reactions from occurring at these functional groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the functional group. The particular removable protecting group employed is not critical.

The definition of “hydroxyl protecting group” includes but is not limited to:

a) Methyl, tert-butyl, allyl, propargyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxy-benzyloxymethyl, p-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, (4-methoxyphenoxy)methyl, gualacolmethyl, tert-butoxymethyl, 4-pentenyloxymethyl, tert-butyidimethylsiloxymethyl, thexyldimethylsiloxymethyl, tert-butyldiphenylsiloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, menthoxymethyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-ethoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl, 1-dianisyl-2,2,2-trichloroethyl, 1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 2-trimethylsilylethyl, 2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydropyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-yl, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and the like;

b) Benzyl, 2-nitrobenzyl, 2-trifluoromethylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-phenylbenzyl, 4-acylaminobenzyl, 4-azidobenzyl, 4-(methylsulfinyl)benzyl, 2,4-dimethoxybenzyl, 4-azido-3-chlorobenzyl, 3,4-dimethoxybenzyl, 2,6-dichlorobenzyl, 2,6-difluorobenzyl, 1-pyrenylmethyl, diphenylmethyl, 4,4′-dinitrobenzhydryl, 5-benzosuberyl, triphenylmethyl (Trityl), α-naphthyidiphenylmethyl, (4-Methoxyphenyl)-diphenyl-methyl, di-(p-methoxyphenyl)-phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)-phenyldiphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′-dimethoxy-3″-[N-(imidazolylmethyl)]trityl, 4,4′-dimethoxy-3″-[N-(imidazolylethyl)carbamoyl]trityl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4′-dimethoxytrityl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl and the like;

c) Trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl, tert-butyidiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl and the like;

d) —C(O)R⁸, where R⁸ is selected from alkyl, substituted alkyl, aryl and more specifically R⁸=hydrogen, methyl, ethyl, tert-butyl, adamantyl, crotyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, methoxymethyl, triphenylmethoxymethyl, phenoxymethyl, 4-chlorophenoxymethyl, phenylmethyl, diphenylmethyl, 4-methoxycrotyl, 3-phenylpropyl, 4-pentenyl, 4-oxopentyl, 4,4-(ethylenedithio)pentyl, 5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy]-4-oxopentyl, phenyl, 4-methylphenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-phenylphenyl, 2,4,6-trimethylphenyl, α-naphthyl, benzoyl and the like;

e) —C(O)OR⁸, where R⁸ is selected from alkyl, substituted alkyl, aryl and more specifically R⁸=methyl, methoxymethyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloromethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, isobutyl, tert-Butyl, vinyl, allyl, 4-nitrophenyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2-(methylthiomethoxy)ethyl, 2-dansenylethyl, 2-(4-nitrophenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl, 2-cyano-1-phenylethyl, thiobenzyl, 4-ethoxy-1-naphthyl and the like.

The definition of “amino protecting group” includes but is not limited to:

a) 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 1-methyl-1-(triphenylphosphonio)ethyl, 1,1-dimethyl-2-cyanoethyl, 2-dansylethyl, 2-(4-nitrophenyl)ethyl, 4-phenylacetoxybenzyl, 4-azidobenzyl, 4-azidomethoxybenzyl, m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl, m-nitrophenyl, 3.5-dimethoxybenzyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, o-nitrobenzyl, α-methylnitropiperonyl, 3,4-dimethoxy-6-nitrobenzyl, N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl. N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl, N-1-(2,2,2-trifluoro-1,1-diphenyl)ethylsulfenyl, N-3-nitro-2-pyridinesulfenyl, N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzene-sulfonyl, N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl and the like;

b) —C(O)OR⁸, where R⁸ is selected from alkyl, substituted alkyl, aryl and more specifically R⁸=methyl, ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl. 9-(2,7-dibromo)fluorenylmethyl, 17-tetrabenzo[a,c,g,i]fluorenylmethyl. 2-chloro-3-indenylmethyl, benz[f]inden-3-ylmethyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothloxanthyl)]methyl, 1,1-dioxobenzo[b]thiophene-2-ylmethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 2-chloroethyl, 1.1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-tert-butylphenyl)-1-methylethyl, 2-(2′-pyridyl)ethyl, 2-(4′-pyridyl)ethyl, 2,2-bis(4′-nitrophenyl)ethyl, N-(2-pivaloylamino)-1,1-dimethylethyl, 2-[(2-nitrophenyl)dithio]-1-phenylethyl, tert-butyl, 1-adamantyl, 2-adamantyl, Vinyl, allyl, 1-Isopropylallyl, cinnamyl. 4-nitrocinnamyl, 3-(3′-pyridyl)prop-2-enyl, 8-quinolyl, N-Hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl, tert-amyl, S-benzyl thiocarbamate, butynyl, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N′-dimethylcarboxamido)benzyl, 1,1-dimethyl-3-(N,N′-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-Iodoethyl, isobornyl, isobutyl, isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1methyl-1-4′-pyridylethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-methylphenyl, 4-(trimethylammonium)benzyl, 2,4,6-trimethylbenzyl and the like.

The definition of “carboxyl protecting group” includes but is not limited to:

2-N-(morpholino)ethyl, choline, methyl, methoxyethyl, 9-Fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl, phenylacetoxymethyl, triisopropylsilylmethyl, cyanomethyl, acetol, p-bromophenacyl. α-methylphenacyl, p-methoxyphenacyl, desyl, carboxamidomethyl, p-azobenzenecarboxamido-methyl, N-phthalimidomethyl, (methoxyethoxy)ethyl, 2,2,2-trichloroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 4-chlorobutyl, 5-chloropentyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2′-pyridyl)ethyl, 2-(p-methoxyphenyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, 2-(4-acetyl-2-nitrophenyl)ethyl, 2-cyanoethyl, heptyl, tert-butyl, 3-methyl-3-pentyl, dicyclopropylmethyl, 2,4-dimethyl-3-pentyl, cyclopentyl, cyclohexyl, allyl, methallyl, 2-methylbut-3-en-2-yl, 3-methylbut-2-(prenyl), 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, propargyl, phenyl, 2,6-dimethylphenyl, 2,6-diisopropylphenyl, 2,6-di-tert-butylmethylphenyl, 2,6-di-tert-butyl-4-methoxyphenyl, p-(methylthio)phenyl, pentafluorophenyl, benzyl, triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl. 5-dibenzosuberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2.6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-Sulfobenzyl, 4-azidomethoxybenzyl, 4-{a/-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzyl, piperonyl, 4-picolyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl, di-tert-butylmethylsilyl, triisopropylsilyl and the like.

The term “Amino acid” refers to any of the naturally occurring amino acids, as well as synthetic analogs and derivatives thereof. Alpha-Amino acids comprise a carbon atom to which is bonded an amino group, a carboxy group, a hydrogen atom, and a distinctive group referred to as a “side chain”. The side chains of naturally occurring amino acids are well known in the art and include, for example, hydrogen (e.g., as in glycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., as in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine), arylalkyl (e.g., as in phenylalanine), substituted arylalkyl (e.g., as in tyrosine), heteroarylalkyl (e.g., as in tryptophan, histidine) and the like. One of skill in the art will appreciate that the term “amino acid” can also include beta-, gamma-, delta-, omega-amino acids, and the like. Unnatural amino acids are also known in the art, as set forth in, Natchus, M. G. Organic Synthesis: Theory and Applications (2001), 5, 89-196; Ager, D. J. Current Opinion in Drug Discovery & Development (2001), 4(6), 800; Reginato, G. Recent Research Developments in Organic Chemistry (2000), 4(Pt. 1), 351-359; Dougherty, D. A. Current Opinion in Chemical Biology (2000), 4(6), 645-652; Lesley, S. A. Drugs and the Pharmaceutical Sciences (2000), 101(Pepfide and Protein Drug Analysis), 191-205; Pojitkov, A. E. Journal of Molecular Catalysis B: Enzymatic (2000), 10(1-3), 47-55; Ager, D. J. Speciality Chemicals (1999), 19(1), 10-12, and all references cited therein. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as alpha, alpha-disubstituted amino acids and other unconventional amino acids may also be suitable components for compounds of the present invention. Examples of unconventional amino acids include: 4-hydroxyproline, 3-methylhistidine, 5-hydroxylysine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline).

The term “N-protected amino acid” refers to any amino acid which has a protecting group bound to the nitrogen of the amino functionality. This protecting group prevents reactions from occurring at the amino functional group and can be removed by conventional chemical or enzymatic steps to reestablish the amino functional group. The particular protecting group employed is not critical.

The term “O-protected amino acid” refers to any amino acid which has a protecting group bound to the oxygen of the carboxyl functionality. This protecting group prevents reactions from occurring at the carboxyl functional group and can be removed by conventional chemical or enzymatic steps to reestablish the carboxyl functional group. The particular protecting group employed is not critical.

The term “ring-closing metathesis catalyst” refers to an organometallic compound that catalyzes the formation of a cyclic molecule from an acyclic precursor in a single synthetic step. The definition of “ring-closing metathesis catalyst” includes but is not limited to: 2,6-diisopropylphenylimidoneophylidene molybdenum (IV) bis-(tert-butoxide), 2,6-diisopropylphenylimidoneophylidene molybdenum (IV) bis-(hexafluoro-tert-butoxide), 2,6-diisopropylphenylimidoneophylidene[racemic-BIPHEN]molybdenum (IV). 2,6-diisopropylphenylimidoneophylidene[(R)-(+)-BIPHEN]molybdenum (IV), 2,6-diisopropylphenylimidoneophylidene[(S)-(−)-BIPHEN]molybdenum (IV), bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, bis-(tricyclohexylphosphine)-3-methyl-2-butenylidene ruthenium (IV) dichloride, bis-(tricyclopentylphosphine)benzylidine ruthenium (IV) dichloride, bis-(tricyclopentylphosphine)-3-methyl-2-butenylidene ruthenium (IV) dichloride, tricyclohexylphosphine-(1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)-benzylidine ruthenium (IV) dichloride, tricyclohexylphosphine-(1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene)-benzylidine ruthenium (IV) dichloride, (1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)-2-isopropoxyphenylmethylene ruthenium (IV) dichloride, (tricyclopentylphosphine)-2-isopropoxyphenylmethylene ruthenium (IV) dichloride, (tricyclopentylphosphine)-2-methoxy-3-naphthylmethylene ruthenium (IV) dichloride, and the like. Such ring-closing metathesis catalysts maybe used by one of ordinary skill and knowledge in the art to produce optically pure compounds from achiral starting materials.

The term “resolving enzyme” refers to a lipase, esterase, peptidase, acylase or protease enzyme of mammalian, plant, fungal or bacterial origin. The source of the “resolving enzyme” includes human pancreas, pig pancreas, pig kidney, pig liver, rabbit liver, wheat germ, Achromobacter sp., Alcaligenes sp., Aspergillus niger, Aspergillus oryzae, Bacillus licheniformis, Bacillus sp., Bacillus thermocatenulatus, Candida antartica type A, Candida antartica type B, Candida lipolytica, Candida rugosa (or Candida cylindracea), E. coli, Geotrichum candidum, Humicola sp., Mucor javanicus (or Rhizomucor javanicus), Mucor miehei (or Rhizomucor miehel), Penicillium camembertil (or Penicillium cyclopium), Penicillium roquefortii, Penicillium sp., Pseudomonas cepacia (or Burkholderia cepacia), Pseudomonas fluorescens, Pseudomonas fragi, Pseudomonas glumae (or Chromobacterium viscosum), Pseudomonas sp., Pseudomonas stutzeri, Rhizopus delemar, Rhizopus javanicus, Rhizopus niveus, Rhizopus oryzae, Thermomyces lanuginose (or Humicola lanuginose) and the like.

The definition of “resolving enzyme” includes but is not limited to:

1. Amano Lipase A (from Aspergillus niger), Amano Lipase M (from Mucor javanicus), Amano Lipase F (from Rhizopus oryzae), Amano Lipase G (from Penicillium camembertii), Amano Lipase R (from Penicillium roquefortii), Amano Newlase F (from Rhizopus niveus), Amano lipase AY (from Candida rugosa), Amano lipase PS (from Pseudomonas cepacia), Amano Lipase AK (from Pseudomonas fluorescens), Amano lipase CHE (from Pseudomonas sp.), Amano Lipase PPL (from pig pancreas), Amano Lipase D (from Rhizopus delemar), Amano Lipase L (from Candida lipolytica), Amano Lipase AH (from Pseudomonas cepacia), Lipase Amano lipase PS-D (immobilized lipase from Pseudomonas cepacia), Amano Lipase PS-C (immobilized lipase from Pseudomonas cepacia) and the like.

2. Roche (cholesterol esterase, lyophilizate, from Candida Rugosa), Roche (cholesterol esterase, sodium chloride solution, from Candida Rugosa), Roche (esterase, suspension, from pig liver), Roche Chirazyme E-1 (esterase, lyophilizate, from pig liver, fraction 1), Roche Chirazyme E-1 (esterase, carrier-fixed, lyophilizate, from pig liver, fraction 1), Roche Chirazyme E-2 (esterase, lyophilizate, from pig liver, fraction 2), Roche Chirazyme L-1 (lipase, from Bacillus thermocatenulatus), Roche Chirazyme L-2 (lipase, solution, from Candida antartica, type B), Roche Chirazyme L-2 (lipase, lyophilizate, from Candida antartica, type B), Roche Chirazyme L-2 (lipase, carrier-fixed, carrier 1, lyophilizate, from Candida antartica, type B), Roche Chirazyme L-2 (lipase, carrier-fixed, carrier 2, lyophilizate, from Candida antartica, type B), Roche Chirazyme L-2 (lipase, carrier-fixed, carrier 3, lyophilizate, from Candida antartica, type B), Roche Chirazyme L-3 (lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, carrier-fixed, carrier 2, lyophilizate, from Candida rugosa), Roche Chirazyme L-5 (lipase, solution, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, lyophilizate, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, carrier-fixed, carrier 1, lyophilizate, from Candida antartica, type A), Roche Chirazyme L-6 (lipase, lyophilizate, from Pseudomonas sp.), Roche Chirazyme L-7 (lipase, lyophilizate, from porcine pancreas), Roche Chirazyme L-8 (lipase, solution, from Thermomyces lanuginosus), Roche Chirazyme L-8 (lipase, lyophilizate, from Thermomyces lanuginosus), Roche Chirazyme L-9 (lipase, solution, from Mucor miehel), Roche Chirazyme L-9 (lipase, lyophilizate, from Mucor miehei), Roche Chirazyme L-9 (lipase, carrier-fixed, carrier 1, dry, from Mucormiehei), Roche Chirazyme L-9 (lipase, carrier-fixed, carrier 2, lyophilizate, from Mucor miehei), Roche Chirazyme L-10 (lipase, lyophilizate, from Alcaligenes sp.), Roche (lipase, from pig pancreas) and the like.

3. Altus Biologics 1 (esterase from pig liver), Altus Biologics 2 (lipase from Pseudomonas cepacia), Altus Biologics 3 (lipase from pig pancreas), Altus Biologics 4 (lipase from Candida rugosa), Altus Biologics 5 (α-chymotrypsin), Altus Biologics 5 (penicillin acylase), Altus Biologics 7 (lipase from Aspergillus niger), Altus Biologics 8 (lipase from Mucor miehel), Altus Biologics 9 (ChiroCLEC™-CR; slurry, lipase, from Candida rugosa), Altus Biologics 10 (Subtilisin Carlsberg), Altus Biologics 11 (lipase from Candida antartica type A), Altus Biologics 12 (lipase from Candida lipolytica), Altus Biologics 13 (lipase from Candida antartica type B), Altus Biologics 14 (lipase from Humicola lanuginosa), Altus Biologics 15 (protease from Bacillus species), Altus Biologics 16 (ChiroCLEC™-BL, slurry, peptidase from Bacillus licheniformis), Altus Biologics 17 (ChiroCLEC™-CR, dry, lipase from Candida rugosa), Altus Biologics 18 (ChiroCLEC™-BL, dry, peptidase from Bacillus licheniformis), Altus Biologics 19 (ChiroCLEC™-PC, slurry, lipase from Pseudomonas cepacia), Altus Biologics 20 (ChiroCLEC™-PC, dry, lipase from Pseudomonas cepacia), Altus Biologics 21 (ChiroCLEC™-EC, slurry, lipase from E. coli), Altus Biologics 22 (ChiroCLEC™-EC, dry, lipase from E. coli), Altus Biologics 23 (lipase from Rhizopus delemar), Altus Biologics 24 (lipase from Rhizopus niveus), Altus Biologics 25 (lipase from Rhizopus oryzae), Altus Biologics 26 (lipase from Pseudomonas glumae), Altus Biologics 27 (lipase from Alcaligenes sp.), Altus Biologics 28 (lipase from Geotrichum candidum), Altus Biologics 29 (lipase from Mucor javanicus), Altus Biologics 30 (protease from Aspergillus oryzae), Altus Biologics 31 (esterase from Candida rugosa), Altus Biologics 41 (protease from Aspergillus niger), Altus Biologics 42 (protease from Aspergillus oryzae), Altus Biologics 43 (protease from Penicillium sp.), Altus Biologics 45 (protease from Aspergillus sp.), Altus Biologics 51, Altus Biologics 52, Altus Biologics 54, Altus Biologics 55.

4. Sigma acylase (from pig kidney), Sigma esterase (solution from pig liver), Sigma esterase (from pig liver), Sigma esterase (from rabbit liver), Sigma lipase (from human pancreas), Sigma lipase (from pig pancreas), Sigma lipase (from wheat germ), Sigma lipase (from Candida rugosa), Sigma lipase (from Mucor javanicus), Sigma lipase (from Mucor miehei), Sigma lipase (from Pseudomonas cepacia), Sigma lipase (from Rhizopus niveus), Sigma lipase (immobilized on cellulose from Pseudomonas sp.), Sigma lipase (from Candida rugosa), Sigma lipase (from Rhizopus arrhizus), Sigma lipase (from Chromobacterium viscosum), Sigma lipase (from Pseudomonas sp.) and the like.

5. Novozym 435 (lipase from Candida antarctica), Novozym™ CALB L (lipase from Candida Antarctica), Lecitase Novo™ (esterase from Aspergillus oryzae), Lecitase Ultra™ (esterase from Thermomyces lanuginosus), Lipozyme™ RM IM (lipase from Rhizomucor miehei), Lipozymem TL 100 L (lipase from Thermomyces lanuginosus), Lipozyme™ TL IM (lipase from Thermomyces lanuginosus) and the like.

6. Meito Sangyo Lipase MY (from Candida cylindracea), Meito Sangyo Lipase OF (from Candida cylindracea), Meito Sangvo Lipase AL (from Achrombacter sp.), Meito Sangyo Lipase ALC/ALG (from Achromobacter sp.), Meito Sangyo Lipase PL (from Alcaligenes sp.), Meito Sangyo Lipase PLC/PLG (from Alcaligenes sp.), Meito Sangyo Lipase QLM (from Alcaligenes sp.), Meito Sangyo Lipase QLC/QLG (from Alcaligenes sp.), Meito Sangyo Lipase SL (from Burkholderia cepacia), Meito Sangyo Lipase TL (from Pseudomonas stutzeri), Meito Sangyo Lipase UL (from Rhizopus sp.) and the like

The term “Prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, “Drug Latentiation” in Jucker, ed. Progress in Drug Research 4:221-294 (1962); Morozowich et al., “Application of Physical Organic Principles to Prodrug Design” in E. B. Roche ed. Design of Biopharmaceutical Properties through Prodrugs and Analogs, APHA Acad. Pharm. Sci. (1977); Bioreversible Carriers in Drug in Drug Design, Theory and Application, E. B. Roche, ed., APHA Acad. Pharm. Sci. (1987); Design of Prodrugs, H. Bundgaard, Elsevier (1985); Wang et al. “Prodrug approaches to the improved delivery of peptide drug” in Curr. Pharm. Design. 5(4):265-287 (1999); Pauletti et al. (1997) Improvement in peptide bioavailability: Peptidomimetics and Prodrug Strategies, Adv. Drug. Delivery Rev. 27:235-256; Mizen et al. (1998) “The Use of Esters as Prodrugs for Oral Delivery of .beta.-Lactam antibiotics,” Pharm. Biotech. 11:345-365; Gaignault et al. (1996) “Designing Prodrugs and Bioprecursors I. Carrier Prodrugs,” Pract. Med. Chem. 671-696; Asghamejad, “Improving Oral Drug Transport”, in Transport Processes in Pharmaceutical Systems, G. L. Amidon, P. 1. Lee and E. M. Topp, Eds., Marcell Dekker, p. 185-218 (2000); Balant et al., “Prodrugs for the improvement of drug absorption via different routes of administration”, Eur. J. Drug Metab. Pharmacokinet., 15(2): 143-53 (1990); Balimane and Sinko, “Involvement of multiple transporters in the oral absorption of nucleoside analogues”, Adv. Drug Delivery Rev., 39(1-3):183-209 (1999); Browne, “Fosphenyloin (Cerebyx)”, Clin. Neuropharmacol. 20(1): 1-12 (1997); Bundgaard, “Bioreversible derivatization of drugs—principle and applicability to improve the therapeutic effects of drugs”, Arch. Pharm. Chemi 86(1): 1-39 (1979); Bundgaard H. “Improved drug delivery by the prodrug approach”, Controlled Drug Delivery 17: 179-96 (1987); Bundgaard H. “Prodrugs as a means to improve the delivery of peptide drugs”, Adv. Drug Delivery Rev. 8(1): 1-38 (1992); Fleisher et al. “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs”, Adv. Drug Delivery Rev. 19(2): 115-130 (1996); Fleisher et al. “Design of prodrugs for improved gastrointestinal absorption by intestinal enzyme targeting”, Methods Enzymol. 112 (Drug Enzyme Targeting, Pt. A): 360-81, (1985); Farquhar D, et al., “Biologically Reversible Phosphate-Protective Groups”, J. Pharm. Sci., 72(3): 324-325 (1983); Freeman S, et al., “Bioreversible Protection for the Phospho Group: Chemical Stability and Bioactivation of Di(4-acetoxy-benzyl) Methylphosphonate with Carboxyesterase,” J. Chem. Soc., Chem. Commun., 875-877 (1991); Friis and Bundgaard, “Prodrugs of phosphates and phosphonates: Novel lipophilic alpha-acyloxyalkyl ester derivatives of phosphate- or phosphonate containing drugs masking the negative charges of these groups”, Eur. J. Pharm. Sci. 4: 49-59 (1996); Gangwar et al., “Pro-drug, molecular structure and percutaneous delivery”, Des. Biopharm. Prop. Prodrugs Analogs, [Symp.] Meeting Date 1976, 409-21. (1977); Nathwani and Wood, “Penicillins: a current review of their clinical pharmacology and therapeutic use”, Drugs 45(6): 866-94 (1993); Sinhababu and Thakker, “Prodrugs of anticancer agents”, Adv. Drug Delivery Rev. 19(2): 241-273 (1996); Stella et al., “Prodrugs. Do they have advantages in clinical practice?”, Drugs 29(5): 455-73 (1985); Tan et al. “Development and optimization of anti-HIV nucleoside analogs and prodrugs: A review of their cellular pharmacology, structure-activity relationships and pharmacokinetics”, Adv. Drug Delivery Rev. 39(1-3): 117-151 (1999); Taylor, “Improved passive oral drug delivery via prodrugs”, Adv. Drug Delivery Rev., 19(2): 131-148 (1996); Valentino and Borchardt, “Prodrug strategies to enhance the intestinal absorption of peptides”, Drug Discovery Today 2(4): 148-155 (1997); Wiebe and Knaus, “Concepts for the design of anti-HIV nucleoside prodrugs for treating cephalic HIV infection”, Adv. Drug Delivery Rev.: 39(1-3):63-80 (1999); Waller et al., “Prodrugs”, Br. J. Clin. Pharmac. 28: 497-507 (1989).

The terms “halogen”, “halide” or “halo” include fluorine, chlorine, bromine, and iodine.

The terms “alkyl” and “substituted alkyl” are interchangeable and include substituted and unsubstituted C₁-C₁₀ straight chain saturated aliphatic hydrocarbon groups, substituted and unsubstituted C₂-C₁₀ straight chain unsaturated aliphatic hydrocarbon groups, substituted and unsubstituted C₄-C₁₀ branched saturated aliphatic hydrocarbon groups, substituted and unsubstituted C₄-C₁₀ branched unsaturated aliphatic hydrocarbon groups, substituted and unsubstituted C₃-C₈ cyclic saturated aliphatic hydrocarbon groups, substituted and unsubstituted C₅-C₈ cyclic unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of “alkyl” shall include but is not limited to: methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, ethenyl, propenyl, butenyl, penentyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, methylcyclopropyl, ethylcyclohexenyl, butenylcyclopentyl, adamantyl, norbornyl and the like. Alkyl substituents are independently selected from the group comprising halogen, —OH, —SH, —NH₂, —CN, —NO₂, ═O, ═CH₂, trihalomethyl, carbamoyl, arylC₀₋₁₀alkyl, heteroarylC₀₋₁₀alkyl, C₁₋₁₀alkyloxy, arylC₀₋₁₀alkyloxy, C₁₋₁₀alkylthio, arylC₀₋₁₀alkylthio, C₁₋₁₀alkylamino, arylC₀₋₁₀alkylamino, N-aryl-N-C₀₋₁₀alkylamino, C₁₋₁₀alkylcarbonyl, arylC₀₋₁₀alkylcarbonyl, C₁₋₁₀alkylcarboxy, arylC₀₋₁₀alkylcarboxy, C₁₋₁₀alkylcarbonylamino, arylC₀₋₁₀alkylcarbonylamino, tetrahydrofuryl, morpholinyl, piperazinyl, hydroxypyronyl, —C₀₋₁₀alkylCOOR₂₁ and —C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selected from hydrogen, alkyl, aryl, or R₂₂ and R₂₃ are taken together with the nitrogen to which they are attached forming a saturated cyclic or unsaturated cyclic system containing 3 to 8 carbon atoms with at least one substituent as defined herein.

The term “alkyloxy” (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. The term “alkyloxyalkyl” represents an alkyloxy group attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

The term “alkylthio” (e.g. methylthio, ethylthio, propylthio, cyclohexenylthio and the like) represents an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge. The term “alkylthioalkyl” represents an alkylthio group attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

The term “alkylamino” (e.g. methylamino, diethylamino, butylamino, N-propyl-N-hexylamino, (2-cyclopentyl)propylamino, hexenylamino, and the like) represents one or two alkyl or substituted alkyl groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The alkyl or substituted alkyl groups maybe taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 10 carbon atoms with at least one substituent as defined above. The term “alkylaminoalkyl” represents an alkylamino group attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

The term “alkylhydrazino” (e.g. methylhydrazino, ethylhydrazino, butylhydrazino, (2-cyclopentyl)propylhydrazino, cyclohexanehydrazino, and the like) represents one alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms attached through a hydrazine bridge. The term “alkylhydrazinoalkyl” represents an alkylhydrazino group attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

The term “alkylcarbonyl” (e.g. cyclooctylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyl and the like) represents an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group. The term “alkylcarbonylalkyl” represents an alkylcarbonyl group attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

The term “alkylcarboxy” (e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy and the like) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen. The term “alkylcarboxyalkyl” represents an alkylcarboxy group attached through an alkyl group as defined above having the indicated number of carbon atoms.

The term “alkylcarbonylamino” (e.g. hexylcarbonylamino, cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl and the like) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen group may itself be substituted with an alkyl or aryl group. The term “alkylcarbonylaminoalkyl” represents an alkylcarbonylamino group attached through an alkyl group as defined above having the indicated number of carbon atoms. The nitrogen group may itself be substituted with an alkyl or arvl group.

The term “alkylcarbonylhydrazino” (e.g. ethylcarbonylhydrazino, tert-butylcarbonylhydrazino and the like) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of a hydrazino group.

The term “aryl” represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 3-phenyl, 4-naphtyl and the like). The aryl substituents are independently selected from the group consisting of halo, —OH, —SH, —CN, —NO₂, trihalomethyl, hydroxypyronyl, C₁₋₁₀alkyl, arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀alkyl, arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl, C₀₋₁₀alkylthioC₀₋₁₀alkyl, arylC₀₋₁₀alkylthioC₀₋₁₀alkyl, C₀₋₁₀alkylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl, N-aryl-N-C⁰⁻¹⁰alkylaminoC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl, C₀₋₁₀alkylcarboxyC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₂₁, and —C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selected from hydrogen, C₁-C₁₀alkyl, arylC₀-C₁₀alkyl, or R₂₂ and R₂₃ are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one substituent as defined above.

The definition of “aryl” includes but is not limited to phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl and the like.

The term “arylalkyl” (e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexenyl and the like) represents an aryl group as defined above attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

The term “arylcarbonyl” (e.g. 2-thiophenylcarbonyl, 3-methoxyanthrylcarbonyl and the like) represents an aryl group as defined above attached through a carbonyl group.

The term “arylalkylcarbonyl” (e.g. (2,3-dimethoxyphenyl)propylcarbonyl, (2-chloronaphthyl)pentenyl-carbonyl, imidazolylcyclopentylcarbonyl and the like) represents an arylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.

The term “aryloxy” (e.g. phenoxy, naphthoxy, 3-methylphenoxy, and the like) represents an aryl or substituted aryl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. The term “aryloxyalkyl” represents an aryloxy group attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

The term “arylthio” (e.g. phenylthio, naphthylthio, 3-bromophenylthio, and the like) represents an aryl or substituted aryl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge. The term “arylthioalkyl” represents an arylthio group attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

The term “arylamino” (e.g. phenylamino, diphenylamino, naphthylamino, N-phenyl-N-naphthylamino, o-methylphenylamino, p-methoxyphenylamino, and the like) represents one or two aryl groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The term “arylaminoalkyl” represents an arylamino group attached through an alkyl group as defined above having the indicated number of carbon atoms. The term “arylalkylamine” represents an aryl group attached through an alkylamino group as defined above having the indicated number of carbon atoms. The term “N-aryl-N-alkylamino” (e.g. N-phenyl-N-methylamino, N-naphthyl-N-butylamino, and the like) represents one aryl and one alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms independently attached through an amine bridge.

The term “arylhydrazino” (e.g. phenylhydrazino, naphthylhydrazino, p-methoxyphenylhydrazino, and the like) represents one aryl or substituted aryl group as defined above having the indicated number of carbon atoms attached through a hydrazine bridge. The term “arylhydrazinoalkyl” represents an arylhydrazino group attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

The term “arylcarbonylamino” (e.g. phenylcarbonylamino, naphthylcarbonylamino and the like) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen group may itself be substituted with an alkyl or aryl group. The term “arylcarbonylaminoalkyl” represents an arylcarbonylamino group attached through an alkyl group as defined above having the indicated number of carbon atoms. The nitrogen group may itself be substituted with an alkyl or aryl group.

The term “arylcarbonylhydrazino” (e.g. phenylcarbonylhydrazino, naphthylcarbonylhydrazino and the like) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of a hydrazino group.

The terms “heteroaryl”, “heterocycle” or “heterocyclic” refers to a monovalent unsaturated group having a single ring or multiple condensed rings, from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring. For the purposes of this application, the terms “heteroaryl”, “heterocycle” or “heterocyclic” do not include carbohydrate rings (i.e. mono- or oligosaccharides).

Unless otherwise constrained by the definition for the “heteroaryl” substituent, such heterocyclic groups can be optionally substituted with 1 to 3 substituents selected from the group comprising: halo, —OH, —SH, —CN, —NO₂, trihalomethyl, hydroxypyronyl, C₁₋₁₀alkyl, arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀alkyl, arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl, C₀₋₁₀alkylthioC₀₋₁₀alkyl, arylC₀₋₁₀alkylthioC₀₋₁₀alkyl, C₀₋₁₀alkylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl, N-aryl-N-C₀₋₁₀alkylaminoC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₂₁, and —C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selected from hydrogen, C₁-C₁₀alkyl, arylC₀-C₁₀alkyl, or R₂₂ and R₂₃ are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one substituent as defined above.

The definition of “heteroaryl” includes but is not limited to thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, pyrrolyl-2,5-dione, 3-pyrrolinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, indolizinyl, indazolyl, phthalimidyl (or isoindoly-1,3-dione), imidazolyl. 2H-imidazolinyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolidinyl-2,5-dione, imidazolidinyl-2,4-dione, 2-thioxo-imidazolidinyl-4-one, imidazolidinyl-2,4-dithione, thiazolidinyl-2,4-dione, 4-thioxo-thiazolidinyl-2-one, piperazinyl-2,5-dione, tetrahydro-pyridazinyl-3,6-dione, 1,2-dihydro-[1,2,4,5]tetrazinyl-3,6-dione, [1,2,4,5]tetrazinanyl-3,6-dione, dihydro-pyrimidinyl-2,4-dione, pyrimidinyl-2,4,6-trione, 1H-pyrimidinyl-2,4-dione, 5-iodo-1H-pyrimidinyl-2,4-dione, 5-chloro-1H-pyrimidinyl-2,4-dione, 5-methyl-1H-pyrimidinyl-2,4-dione, 5-isopropyl-1H-pyrimidinyl-2,4-dione, 5-propynyl-1H-pyrimidinyl-2,4-dione, 5-trifluoromethyl-1H-pyrimidinyl-2,4-dione, 6-amino-9H-purinyl, 2-amino-9H-purinyl, 4-amino-1H-pyrimidinyl-2-one, 4-amino-5-fluoro-1H-pyrimidinyl-2-one, 4-amino-5-methyl-1H-pyrimidinyl-2-one, 2-amino-1,9-dihydro-purinyl-6-one, 1,9-dihydro-purinyl-6-one, 1H-[1,2,4]triazolyl-3-carboxylic acid amide, 2,6-diamino-N₆-cyclopropyl-9H-purinyl, 2-amino-6-(4-methoxyphenylsulfanyl)-9H-purinyl, 5,6-dichloro-1H-benzoimidazolyl, 2-isopropylamino-5,6-dichloro-1H-benzoimidazolyl, 2-bromo-5,6-dichloro-1H-benzoimidazolyl, and the like.

The term “saturated heterocyclic” represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic saturated heterocyclic group covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 1-piperidinyl, 4-piperazinyl and the like).

The saturated heterocyclic substituents are independently selected from the group consisting of halo, —OH, —SH, —CN, —NO₂, trihalomethyl, hydroxypyronyl, C₁₋₁₀alkyl, arylC₀₋₁₀alkyl, C₀₋₁₀alkyloxyC₀₋₁₀alkyl, arylC₀₋₁₀alkyloxyC₀₋₁₀alkyl, C₀₋₁₀alkylthioC₀₋₁₀alkyl, arylC₀₋₁₀alkylthioC₀₋₁₀alkyl, C₀₋₁₀alkylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylaminoC₀₋₁₀alkyl, N-aryl-N—C₀₋₁₀alkylaminoC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarbonylC₀₋₁₀alkyl, C₁₋₁₀alkylcarboxyC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarboxyC₀₋₁₀alkyl, C₁₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, arylC₀₋₁₀alkylcarbonylaminoC₀₋₁₀alkyl, —C₀₋₁₀alkylCOOR₂₁, and —C₀₋₁₀alkylCONR₂₂R₂₃ wherein R₂₁, R₂₂ and R₂₃ are independently selected from hydrogen, C₁-C₁₀alkyl, arylC₀-C₁₀alkyl, or R₂₂ and R₂₃ are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one substituent as defined above.

The definition of saturated heterocyclic includes but is not limited to pyrrolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithienyl, thiomorpholinyl, piperazinyl, quinuclidinyl and the like.

The term “alpha-beta-unsaturated carbonyl” refers to a molecule that has a carbonyl group directly attached to a double or triple bonded carbon and which would be obvious to one of ordinary skill and knowledge in the art. The definition of alpha-beta-unsaturated carbonyl heterocyclic includes but is not limited to acrolein, methylvinyl ketone, and the like.

The term “acetal” refers to a molecule that contains a carbon atom C₁ that is directly attached to a hydrogen atom (H₁), a substituted carbon atom (C₂) and two oxygen atoms (Or and O₂). These oxygen atoms are in turn attached to other substituted carbon atoms (C₃ and C₄), which would be obvious to one of ordinary skill and knowledge in the art. The definition of acetal includes but is not limited to 1,1-dimethoxypropane, 1,1-bis-allyloxybutane and the like.

The term “cyclic acetal” refers to an acetal as defined above where C₃ and C₄, together with the oxygen atoms to which they are attached, combine thru an alkyl bridge to form a 5- to 10-membered ring, which would be obvious to one of ordinary skill and knowledge in the art. The definition of cyclic acetal includes but is not limited to 2-methyl-[1,3]dioxolane, 2-ethyl-[1,3]dioxane, 2-phenyl-[1,3]dioxane, 2 2-phenyl-hexahydro-pyrano[3,2-d][1,3]dioxine and the like.

The term “ketal” refers to a molecule that contains a carbon atom C₁ that is directly attached to two substituted carbon atom (C₂ and C₃) and two oxygen atoms (O₁ and O₂). These oxygen atoms are in turn attached to other substituted carbon atoms (C₄ and C₅), which would be obvious to one of ordinary skill and knowledge in the art. The definition of acetal includes but is not limited to 2,2-dimethoxy-butane, 3,3-diethoxy-pentane and the like.

The term “cyclic ketal” refers to a ketal as defined above where C₄ and C₅, together with the oxygen atoms to which they are attached, combine thru an alkyl bridge to form a 5- to 10-membered ring, which would be obvious to one of ordinary skill and knowledge in the art. The definition of cyclic acetal includes but is not limited to 2,2,4,5-tetramethyl-[1,3]dioxolane, 2,2-diethyl-[1,3]dioxepane, 2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine and the like.

DETAILED DESCRIPTION

In one embodiment, the present invention provides a process for preparing a compound of formula G. Such a process can be performed, for example, by contacting a compound of formula C with a compound of formula F under conditions suitable to form compound of formula G, as set forth below:

In the scheme shown above, R₁ is typically alkyl, substituted alkyl, or aryl; R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl and aryl; R₃, R₄, R₆ and R₇ are either all hydrogen or, of R₃, R₄, R₆ and R₇, three are hydrogen and the fourth is alkyl, substituted alkyl, or aryl. In one embodiment, R₁ is ethyl and R₂, R₃, R₄, R₆, and R₇ are hydrogen. In another embodiment, R₁ is ethyl, R₆ is methyl, and R₂, R₃, R₄, R₆, and R₇ are hydrogen. In still another embodiment, R₁ is ethyl, R₅ is phenyl, and R₂, R₃, R₄, R₆, and R₇ are hydrogen.

Solvents contemplated for use in the practice of this particular invention process are typically ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran, and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about −100° C. up to about 30° C.

Compound C is typically contacted with compound F In the presence of an organometallic reagent. Organometallic reagents contemplated for use include, for example, lithium diisopropyl amide, tert-butyl lithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropyl amide-spartein complex, triethyl amine-dicyclohexyl boron triflate complex, and the like.

In yet another embodiment of the invention, there are provided compounds having the structure G:

wherein:

-   -   R₁ is alkyl, substituted alkyl, or aryl, R₂ and R₅ are each         independently hydrogen, alkyl, substituted alkyl and aryl; R₃,         R₄, R₆ and R₇ are either all hydrogen or, of R₃, R₄, R₆ and R₇,         three are hydrogen and the fourth is alkyl, substituted alkyl,         or aryl. In one embodiment, R. Is ethyl and R₂, R₃, R₄, R₅, R₆,         and R₇ are hydrogen.

Invention compounds having structure G maybe optically pure and include (2R,3R)-2-allyloxy-3-hydroxy-pent-4-enoic acid ethyl ester; (2S,3S)-2-allyloxy-3-hydroxy-pent-4-enoic acid ethyl ester; (2R,3S)-2-allyloxy-3-hydroxy-pentenoic acid ethyl ester; and (2S,3R)-2-allyloxy-3-hydroxy-pent-4-enoic acid ethyl ester.

In one embodiment, the present invention provides a process for preparing a compound of formula H. Such a process can be performed, for example, by contacting a compound of formula G under conditions suitable to form compound of formula H, as set forth below:

In the scheme shown above, R₁ is typically alkyl, substituted alkyl, or aryl; R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl and aryl; R₃, R₄, R₆ and R₇ are either all hydrogen or, of R₃, R₄, R₆ and R₇, three are hydrogen and the fourth is alkyl, substituted alkyl, or aryl; R₉ is hydrogen, alkyl, substituted alkyl, aryl or hydroxyl protecting group. In another embodiment, R₁ is ethyl, and R₂, R₃, R₄, R₅, R₆, R₇ and R₉ are hydrogen. In another embodiment, R₁ is ethyl, R₆ is methyl, and R₂, R₃, R₄, R₆, R₇ and R₉ are hydrogen. In still another embodiment, R₁ is ethyl, R₆ is phenyl, and R₂, R₃, R₄, R₆, R₇ and R₉ are hydrogen.

In one embodiment, the present invention provides a process for preparing compound of formula H as a mixture of stereoisomers, such as for example, cis or trans stereoisomers and the like. In another embodiment, the invention provides a process for separating such stereoisomers, such as for example, chromatography, crystallization, re-crystallization, distillation and the like. In still another embodiment, the invention provides a process for preparing compound H as an optically pure isomer.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 150° C.

Compound G Is typically contacted with a ring-closing metathesis catalyst. Ring-closing metathesis catalysts contemplated for use include, for example, 2,6-diisopropylphenylimidoneophylidene molybdenum (IV) bis-(tert-butoxide), 2,6-diisopropylphenylimidoneophylidene molybdenum (IV) bis-(hexafluoro-tert-butoxide), 2,6-diisopropylphenylimidoneophylidene[racemic-BIPHEN]molybdenum (IV), 2,6-diisopropylphenylimidoneophylidene[(R)-(+)-BIPHEN]molybdenum (IV), 2,6-diisopropylphenylimidoneophylidene[(S)-(−)-BIPHEN]molybdenum (IV), bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, bis-(tricyclohexylphosphine)-3-methyl-2-butenylidene ruthenium (IV) dichloride, bis-(tricyclopentylphosphine)benzylidine ruthenium (IV) dichloride, bis-(tricyclopentylphosphine)-3-methyl-2-butenylidene ruthenium (IV) dichloride, tricyclohexylphosphine-(1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)-benzylidine ruthenium (IV) dichloride, tricyclohexylphosphine-(1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene)-benzylidine ruthenium (IV) dichloride, (1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)-2-isopropoxyphenylmethylene ruthenium (IV) dichloride, (tricyclopentylphosphine)-2-isopropoxyphenylmethylene ruthenium (IV) dichloride, (tricyclopentylphosphine)-2-methoxy-3-naphthylmethylene ruthenium (IV) dichloride and the like.

In yet another embodiment of the invention, there are provided compounds having the structure H:

wherein:

-   -   R₁ is alkyl, substituted alkyl, or aryl; R₂ and R₅ are each         independently hydrogen, alkyl, substituted alkyl and aryl; R₉ is         hydrogen, alkylcarbonyl, substituted alkylcarbonyl, arylcarbonyl         or hydroxyl protecting group.

Invention compounds having structure H maybe optically pure and include 3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2R,3)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2S,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2S,3R)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2R,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2R,3R) 3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2S,3S) 3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2R,3S) 3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2S,3R) 3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

In one embodiment, the present invention provides a process for preparing a compound of formula H. Such a process can be performed, for example, by contacting a compound of formula I with a resolving enzyme and an acylating agent under conditions suitable to form compound of formula H, as set forth below:

In the scheme shown above, R₁ is typically alkyl, substituted alkyl, or aryl; R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl and aryl; R₁ is hydrogen, alkylcarbonyl, substituted alkylcarbonyl, or arylcarbonyl. In another embodiment, R₁ is ethyl, R₂ and R₅ are hydrogen, and R₉ is hydrogen or acetyl.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 40° C.

Compound I is typically contacted with a resolving enzyme in the presence of an acylating agent. Resolving enzymes contemplated for use include lipase, esterase, peptidase, acylase or protease enzymes of mammalian, plant, fungal or bacterial origin, such as for example, Lipase Amano lipase PS-4 (immobilized lipase from Pseudomonas cepacia), Amano Lipase PS-C (immobilized lipase from Pseudomonas cepacia), Roche Chirazyme L-3 (lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, carrier-fixed, carrier 2, lyophilizate, from Candida rugosa), Roche Chirazyme L-5 (lipase, solution, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, lyophilizate, from Candida antarfica, type A), Roche Chirazyme L-5 (lipase, carrier-fixed, carrier 1, lyophilizate, from Candida antartica, type A), Roche Chirazyme L-10 (lipase, lyophilizate, from Alcaligenes sp.), Altus Biologics 8 (lipase from Mucormiehei) and Altus Biologics 27 (lipase from Alcaligenes sp.) and the like. Acylating agents contemplated for use include, for example, ethyl acetate, vinyl acetate, vinyl propionate, vinyl butyrate, isopropenyl acetate, 1-ethoxyvinyl acetate, trichloroethyl butyrate, trifluoroethyl butyrate, trifluoroethyl laureate, S-ethyl thiooctanoate, biacetyl monooxime acetate, acetic anhydride, succinic anhydride, amino acid, diketene and the like.

In one embodiment, the present invention provides a process for preparing compound of formula H as a mixture of optically pure compounds, such as for example, a mixture of (2R,3R) 3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester and (2S,3S) 3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, or a mixture of (2S,3R) 3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester and (2R,3S) 3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester. In another embodiment, the invention provides a process for separating such optically pure compounds, such as for example, chromatography, crystallization, re-crystallization, distillation and the like.

In one embodiment, the present invention provides a process for preparing a compound of formula J. Such a process can be performed, for example, by contacting a compound of formula H under conditions suitable to form compound of formula J, as set forth below:

In the scheme shown above, R₁ is typically alkyl, substituted alkyl, or aryl; R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl and aryl; R₉ is hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl or hydroxyl protecting group. In another embodiment, R₁ is ethyl, R₂ and R₅ are hydrogen, and R₉ is hydrogen or acetyl.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as dichloromethane and the like, alcoholic solvents, such as for example 2-methyl-2-propanol and the like, ethereal solvents, such as for example tetrahydrofuran and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about −78° C. up to about 60° C.

Compound H is typically contacted with a suitable mixture of an oxidant, a co-oxidant and a ligand, or any suitable mixtures thereof. Oxidants contemplated for use include, for example, osmium tetroxide, potassium permanganate, thallium acetate, potassium periodate, silver acetate and the like, co-oxidants contemplated for use include, for example, N-methylmorpholine oxide, trimethylamine oxide, tert-butyl peroxide, iodine, potassium ferricyanide and the like, ligands contemplated for use include, for example, pyridine, quinuclidine, dihydroquinine acetate, dihydroquinidine acetate, dihydroquinine anthraquinone-1,4-diyl diether ((DHQ)₂AQN), dihydroquinine phthalazine-1,4-diyl diether ((DHQ)₂PHAL), dihydroquinine 2,5-diphenyl-4,6-pyrimidinedlyl diether ((DHQ)₂PYR), dihydroquinidine anthraquinone-1,4-diyl diether ((DHQD)₂AQN), dihydroquinidine phthalazine-1,4-diyl diether ((DHQD)₂PHAL), dihydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQD)₂PYR), tetraethyl ammonium hydroxide, tetraethyl ammonium acetate, N,N,N′N′-tetramethylethylene diamine (TMEDA) and the like.

In yet another embodiment of the invention, there are provided compounds having the structure J:

wherein:

-   -   R₁ is hydrogen, alkyl, substituted alkyl, or aryl; R₂ and R₅ are         each independently hydrogen, alkyl, substituted alkyl, and aryl;         R₉ is hydrogen, alkyl, substituted alkyl, substituted         alkylcarbonyl, alkylcarbonyl, aryl, arylcarbonyl or hydroxyl         protecting group.     -   With the proviso that:         -   stereoisomers (2R,3R,4S,5S), (2R,3S,4S,5R), (2R,3R,4R,5R),             (2R,3R,4S,5R), (2S,3R,4R,5R) cannot have R₁=hydrogen or             methyl and R₂=R₅=R₉=hydrogen; and, stereoisomer             (2S,3S,4R,5R) cannot have R₁=hydrogen or methyl and             R₂=R₅=R₉=hydrogen;

Invention compounds having structure J maybe optically pure and include (1R,2R,3R,4R) 3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1R,2R,3S,4S) 3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1S,2S,3R,4R) 3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1S,2S,3S,4S) 3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1R,2S,3R,4R) 3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1R,2S,3S,4S) 3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1S,2R,3R,4R) 3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1S,2R,3S,4S) 3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1R,2R,3R,4R) 3-4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1R,2R,3S,4S) 3-4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1S,2S,3R,4R) 3-4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1S,2S,3S,4S) 3-4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1R,2S,3R,4R) 3-4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1R,2S,3S,4S) 3-4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; (1S,2R,3R,4R) 3-4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester; and (1S,2R,3S,4S) 3-4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester.

In one embodiment, the present invention provides a process for preparing a compound of formula K. Such a process can be performed, for example, by contacting a compound of formula J under conditions suitable to form a compound of formula K, as set forth below:

In the scheme shown above, R₁ is typically alkyl, substituted alkyl, or aryl; R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl and aryl; R₉, R₁₀ and R₁₁ are each independently hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl and hydroxyl protecting group.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 40° C.

Compound J is typically contacted with a resolving enzyme in the presence of an acylating agent. Resolving enzymes contemplated for use include lipase, esterase, peptidase, acylase or protease enzymes of mammalian, plant, fungal or bacterial origin, such as for example, Lipase Amano lipase PS-D (immobilized lipase from Pseudomonas cepacia), Amano Lipase PS-C (immobilized lipase from Pseudomonas cepacia), Roche Chirazyme L-3 (lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, carrier-fixed, carrier 2, lyophilizate, from Candida rugosa), Roche Chirazyme L-5 (lipase, solution, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, lyophilizate, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, carrier-fixed, carrier 1, lyophilizate, from Candida antartica, type A), Roche Chirazyne L-10 (lipase, lyophilizate, from Alcaligenes sp.), Altus Biologics 8 (lipase from Mucor miehei) and Altus Biologics 27 (lipase from Alcaligenes sp.) and the like. Acylating agents contemplated for use include, for example, ethyl acetate, vinyl acetate, vinyl propionate, vinyl butyrate, isopropenyl acetate, 1-ethoxyvinyl acetate, trichloroethyl butyrate, trifluoroethyl butyrate, trifluoroethyl laureate, S-ethyl thiooctanoate, biacetyl monooxime acetate, acetic anhydride, succinic anhydride, amino acid, diketene and the like.

Compound J can also be contacted with an electrophilic reagent. Electrophilic reagents contemplated for use include, for example, diazomethane, trimethylsilyldiazomethane, alkyl halides, such as for example methyl iodide, benzyl bromide and the like, alkyl triflates, such as for example methyl triflate and the like, alkyl sulfonates, such as for example ethyl toluenesulfonate, butyl methanesulfonate and the like, acyl halides, such as for example acetyl chloride, benzoyl bromide and the like, acid anhydrides, such as for example acetic anhydride, succininc anhydride, maleic anhydride and the like, isocyanates, such as for example methyl isocyanate, phenylisocyanate and the like, chloroformates, such as for example methyl chloroformate, ethyl chloroformate, benzyl chloroformate and the like, sulfonyl halides, such as for example methanesulfonyl chloride, p-tolunesulfonyl chloride and the like, silyl halides, such as for example trimethylsilyl chloride, tertbutyidimethyl silyll chloride and the like, phosphoryl halide such as for example dimethyl chlorophosphate and the like, alpha-beta-unsaturated carbonyl such as for example acrolein, methyl vinyl ketone, cinnamaldehyde and the like.

Compound J can also be contacted with an alcohol in the presence of an azodicarboxylate and a phosphine base, or any suitable mixtures thereof. Azodicarboxylates contemplated for use include, for example, diethyl azodicarboxylate, dicyclohexyl azodicarboxylate, diisopropyl azodicarboxylate and the like. Phosphine bases contemplated for use include, for example, triethylphosphine, tricyclopentylphosphine, tricyclohexylphosphine, triphenylphosphine, tri-o-tolylphosphine, and the like.

Compound J can also be contacted with a carboxylic acid or an amino acid in the presence of a coupling agent and a base, or any suitable mixtures thereof. Coupling agents contemplated for use include, for example, dicyclohexylcarbodiimide (DCC), diisopropyl carbodiiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDCl), N-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 4-nitrophenol, pentafluorophenol, 2-(1H-benzotriazole-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), O-benzotriazole-N,N,N′N′-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy-tris-(dimethylaminoyphosphonium hexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate, bromo-trispyrrolidino-phosphonium hexafluorophosphate, 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), 0-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), tetramethylfluoroformamidinium hexafluorophosphate and the like. Bases contemplated for use include, for example, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like.

In another embodiment, the present invention provides a process for preparing compound of formula K as a mixture of optically pure compounds, such as for example, (2R,3R,4R,5R)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester and (2R,3R,4S,5S-3,5-diacetoxy-4-hydroxy-tetrahydropyran-2-carboxylic acid ethyl ester. In another embodiment, the invention provides a process for separating such optically pure compounds, such as for example, chromatography, crystallization, re-crystallization, distillation and the like.

In yet another embodiment of the invention, there are provided compounds having the structure K:

wherein:

-   -   R₁ is alkyl, substituted alkyl, or aryl; R₂ and R₅ are each         independently hydrogen, alkyl, substituted alkyl and aryl; R₉,         R₁₀ and R₁₁ are each independently hydrogen, alkyl, substituted         alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl,         arylcarbonyl and hydroxyl protecting group.     -   With the proviso that         -   stereoisomers (2R, 3R, 4S, 5S), (2R, 3S, 4S, 5R), (2R, 3R,             4R, 5R), (2R, 3R, 4S, 5R), (2S, 3R, 4R, 5R), (2S, 3S, 4R,             5S), (2R, 3S, 4R, 5S) cannot have R₁=methyl and             R₂=R₅=hydrogen and R₉=R₁₀=R₁₁=acetyl; stereoisomers (2R, 3R,             4S, 5S), (2R, 3S, 4S, 5R), (2R, 3R, 4R, 5R), (2R, 3R, 4S,             5R), (2S, 3R, 4R, 5R), (2S, 3S, 4R, 5R) cannot have             R₁=methyl and R₂=R₅=R₉=R₁₀=R₁₁=hydrogen; stereolsomers (2R,             3R, 4S, 5S), (2R, 3S, 4S, 5R), (2R, 3R, 4R, 5R), (2R, 3R,             4S, 5R), (2S, 3R, 4R, 5R), (2S, 3S, 4R, 5R) cannot have             R₁=R₂=R₅=R₉=R₁₀=R₁₁=hydrogen; stereoisomers (2S, 3S, 4R,             5R), (2R, 3S, 4R, 5R) cannot have R₁=R₁₀=R₁₁=methyl and             R₂=R₅=hydrogen and R₉=acetyl; stereoisomers (2S, 3S, 4R,             5R), (2R, 3S, 4R, 5R) cannot have R₁=R₁₀=R₁₁=methyl and             R₂=R₅=hydrogen and R₉=benzoyl; stereoisomer (2S, 3R, 4R, 5S)             cannot have R₁=R₂=R₅=hydrogen and R₉=R₁₀=R₁₁=acetyl; and             stereoisomer (1S, 4R, 5R, 8S) cannot have R₁=methyl             R₂=R₅=R₁₁=hydrogen and R₉=R₁₀=benzyl.

In one embodiment, the present invention provides a process for preparing a compound of formula L. Such a process can be performed, for example, by contacting a compound of formula K under conditions suitable to form a compound of formula L, as set forth below:

In the scheme shown above, R₁ is typically alkyl, substituted alkyl, or aryl; R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl and aryl; R₉ and R₁₀ are each independently hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl and hydroxyl protecting group; R₁₁ is hydrogen.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 200° C.

In one embodiment, compound K is contacted with focused microwave radiation. The process is typically carried out using a quartz reactor at a pressure in the range of about 1 atm to about 25 atm and a power setting in the range of about 1 W per liter of solvent to about 900 W per liter of solvent.

In another embodiment, compound K is contacted with a dehydrating reagent in the presence or absence of a base. Dehydrating reagents contemplated for use include, for example, acetic acid, hydrochloric acid, sulfuric acid, toluenesulfonic acid, acetyl chloride, benzoyl chloride, oxalyl chloride, acetic anhydride, methyl chloroformate, dicyclohexylcarbodiimide, diethyl azodicarboxylate, 2,4,6-trichloro-[1,3,5]triazine, dibutyltin oxide, dibutyltin chloride, zinc chloride, molecular sieves, silica gel, alumina, catechol borane, mercuric acetate, silver perchlorate and the like. Bases contemplated for use include, for example, pyridine, triethylamine, diisopropylethylamine, triphenylphosphine, imidazole, tert-butyl lithium, tert-butyl magnesium chloride, potassium hydride, sodium hydride, potassium tert-butoxide, sodium methoxide, potassium carbonate, potassium bicarbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide and the like.

In yet another embodiment of the invention, there are provided compounds having the structure L:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl and aryl; R₉ and R₁₀ are each independently hydrogen,         alkyl, substituted alkyl, alkylcarbonyl, substituted         alkylcarbonyl, aryl, arylcarbonyl and hydroxyl protecting group.     -   With the proviso that:         -   stereoisomer (1S, 4R, 5R, 8S) cannot have             R₂=R₅=R₉=R₁₀=hydrogen; stereoisomer (1S, 4R, 5R, 8S) cannot             have R₂=R₅=R₁₀=hydrogen and R₉=benzoyl; stereoisomer (1S,             4R, 5R, 8S) cannot have R₂=R=hydrogen and R₉=R₁₀=benzoyl;             stereoisomer (1S, 4R, 5R, 8S) cannot have R₂=hydrogen and             R₉=R₁₀=benzyl

Invention compounds having structure L maybe optically pure and include (1R,4S,5S,8R)-8-acetoxy-4-hydroxy-2,6-dioxa-bicyclo[3.2. I]octan-7-one and (1R,4S,5S,8R)-4,8-hydroxy-2,6-dioxa-bicyclo[3.2.1]octan-7-one.

In one embodiment, the present invention provides a process for preparing a compound of formula M. Such a process can be performed, for example, by contacting a compound of formula L with a nucleophile under conditions suitable to form a compound of formula M, as set forth below:

R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl and aryl; R₉ and R₁₀ are each independently hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl and hydroxyl protecting group; R₁₂ is typically alkyl, substituted alkyl, aryl, hydroxy, alkyloxy, substituted alkyloxy, aryloxy, amino, alkylamino, arylamino, hydrazine, alkylhydrazino, arylhydrazino, alkylcarbonylhydrazino, arylcarbonylhydrazino, nitrogen containing saturated heterocyclic compound, O-protected amino acid, or solid support; with the proviso that compound of formula L cannot be the stereoisomer (1S,4R,5R,8S) where R₂=R₅=hydrogen and R₉=R₁₀=benzyl and R₁₂=methoxy.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 150° C.

Compound L is typically contacted with a nucleophile in the presence or absence of a Lewis acidic reagent. Nucleophiles contemplated for use include, for example, water, potassium hydroxide, methanol, sodium ethoxide, benzyl alcohol, 3,5-dimethylphenol, sodium phenoxide, ethyl thiol, potassium phenyl thiolate, ammonia, ammonium hydroxide, methylamine, benzylamine, dibutylamine, aniline, 3-methoxyaniline, diphenylamine, sodium amide, Lithium dimethylamide, potassium benzylmethylamide, lithium anilide, hydrazine, potassium hydrizide, methylhydrazine, phenylhydrazine, benzoylhydrazine, acetylhydrazine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, lithium piperidide, potassium morpholinide, glycine methyl ester, serine tert-butyl ester, valine ethyl ester lithium salt, methyl lithium, ethyl magnesium bromide, phenyl lithium, diethyl zinc, diethyl mercury, trimethyl aluminum, triethyl indium, trimethyl gallium, Merrifield resin, Wang resin, Rink resin, Wang resin lithium salt and the like. Lewis acidic reagents contemplated for use include, for example, boron trifluoride, boron trifluoride etherate, boron trifluoride tetrahydrofuran complex, boron trifluoride tert-butyl-methyl ether complex, boron trifluoride dibutyl ether complex, boron trifluoride dihydrate, boron trifluoride di-acetic acid complex, boron trifluoride dimethyl sulfide complex, boron trichloride, boron trichloride dimethyl sulfide complex, boron tribromide, boron tribromide dimethyl sulfide complex, boron triiodide, trimethoxyborane, triethoxyborane, trimethylaluminum, triethylaluminum, aluminum trichloride, aluminum trichloride tetrahydrofuran complex, aluminum tribromide, titanium tetrachloride, titanium tetrabromide, titanium iodide, titanium tetraethoxide, titanium tetraisopropoxide, scandium (III) trifluoromethanesulfonate, yttrium (III) trifluoromethanesulfonate, ytterbium (III) trifluoromethanesulfonate, lanthanum (Ill) trifluoromethanesulfonate, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, zinc (II) trifluoromethanesulfonate, zinc (II) sulfate, magnesium sulfate, lithium perchlorate, copper (II) trifluoromethanesulfonate, copper (II) tetrafluoroborate and the like.

In yet another embodiment of the invention, there are provided compounds having the structure M:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl and aryl; R₉ and R₁₀ are each independently hydrogen,         alkyl, substituted alkyl, alkylcarbonyl, substituted         alkylcarbonyl, aryl, arylcarbonyl and hydroxyl protecting group;         R₁₂ is alkyl, substituted alkyl, aryl, hydroxy, alkyloxy,         substituted alkyloxy, aryloxy, amino, alkylamino, arylamino,         nitrogen containing saturated heterocyclic compound, O-protected         amino acid, or solid support.     -   With the proviso that         -   stereoisomers (2R, 3R, 4S, 5S), (2R, 3S , 4S, 5R), (2R, 3R,             4R, 5R), (2R, 3R, 4S, 5R), (2S, 3R, 4R, 5R), (2S, 3S, 4R,             5R) cannot have R₁₂=hydroxy and R₂→R₅=R₉=R₁₀=hydrogen;             stereoisomers (2R, 3R, 4S, 5S), (2R, 3S,4S, 5R), (2R, 3R,             4R, 5R), (2R, 3R, 4S, 5R), (2S, 3R, 4R, 5R), (2S, 3S, 4R,             5R) cannot have R₁₂=methoxy and R₂=R₅=R₉=R₁₀=hydrogen;             stereoisomers (2R, 3R, 4S, 5S), (2R, 3S, 4S, 5R), (2R, 3R,             4R, 5R), (2R, 3R, 4S, 5R), (2S, 3R, 4R, 5R), (2S, 3S, 4R,             5S) cannot have R₁₂=amino and R₂=R₅=R₉=R₁₀=hydrogen; and,             stereoisomer (1S, 4R, 5R, 8S) cannot have R₂=R₅=hydrogen and             R₉=R₁₀=benzyl and R₁₂=methoxy.

In one embodiment, the present invention provides a process for preparing a compound of formula N. Such a process can be performed, for example, by contacting a compound of formula H under conditions suitable to form a compound of formula N, as set forth below:

R₁ is typically alkyl, substituted alkyl, or aryl; R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl and aryl; R₉ is hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or hydroxyl protecting group. In another embodiment, R₁ is ethyl, R₂, R₅ and R₉ are hydrogen. In still another embodiment, R₁ is ethyl, R₂ and R₅ are hydrogen, and R₉ is acetyl.

Solvents contemplated for use in the practice of this particular invention process are typically water, ammonia, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol, 1,2-ethanediol, polyethylene glycol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about −100° C. up to about 100° C.

Compound H is typically contacted with a reducing reagent in the presence or absence of an acidic reagent or a Lewis acidic reagent. Reducing reagents contemplated for use include, for example, borane-dimethyl sulfide complex, 9-borabicyclo[3.3.1.]nonane (9-BBN), catechol borane, lithium borohydride, sodium borohydride, sodium borohydride-methanol complex, potassium borohydride, sodium hydroxyborohydride, lithium triethylborohydride, lithium n-butylborohydride, sodium cyanoborohydride, calcium (II) borohydride, lithium aluminum hydride, diisobutylaluminum hydride, n-butyl-diisobutylaluminum hydride, sodium bis-methoxyethoxyaluminum hydride, triethoxysilane, diethoxymethylsilane, lithium hydride, lithium, sodium, hydrogen NUB, and the like. Acidic reagents contemplated for use include, for example, acetic acid, methanesulfonic acid, hydrochloric acid, and the like. Lewis acidic reagents contemplated for use include, for example, trimethoxyborane, triethoxyborane, aluminum trichloride, lithium chloride, vanadium trichloride, dicyclopentadienyl titanium dichloride, cesium fluoride, potassium fluoride, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, and the like.

In yet another embodiment of the invention, there are provided compounds having the structure N:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl,         alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or         hydroxyl protecting group     -   With the proviso that:         -   stereoisomers (2R,3S), (2S,3R) and (2R,3R) cannot have             R₂=R₉=hydrogen.

Invention compounds having structure N maybe optically pure and include (2S,3S-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol).

In yet another embodiment of the invention, there are provided compounds having the structure O:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₉ is alkyl, substituted alkyl, alkylcarbonyl,         substituted alkylcarbonyl, aryl, arylcarbonyl, or hydroxyl         protecting group; R₁₃ is hydrogen, alkyl, substituted alkyl,         aryl, alkylcarbonyl, arylcarbonyl, or hydroxyl protecting group.     -   With the proviso that         -   stereoisomers (2R,3S), (2S,3R) and (2R,3R) cannot have             R₉=R₁₃=acetyl; stereoisomer (2R,3S) cannot have             R₉=2-bromoallyl and R₁₃=tert-butyldimethylsilyl;             stereoisomer (2R,3S) cannot have R₉=2-bromobenzyl and             R₁₃=tert-butyldimethylsilyl; stereoisomer (2R,3S) cannot             have R₉=2-bromocyclopent-1-ene and             R₁₃=tert-butyldimethylsilyl; stereoisomer (2R,3S) cannot             have R₉=2-bromocyclohex-1-ene and             R₁₃=tert-butyldimethylsilyl; stereoisomer (2R,3S) cannot             have R₉=tichloromethylimidate [C(═NH)CCl₃] and R₁₃=acetyl;             stereoisomer (2R,3S) cannot have R₉=trichloromethylimidate             [C(═NH)CCl₃] and R₁₃=tert-butyldimethylsilyl; stereoisomer             (2R,3S) cannot have             R₉=4-methoxyphenylaminocarboxy[4-CH₃OC₆H₄NHC(═O)] and             R₁₃=benzoyl; stereoisomer (2R,3S) cannot have             R₉=4-methoxyphenylaminocarboxy[4-CH₃OC₆H₄NHC(═O)] and             R₁₃=tert-butyldimethylsilyl; stereoisomer (2S,3R) cannot             have R₉=allyl and R₁₃=tosyl; stereoisomer (2R,3R) cannot             have R₉=R₁₃=benzoyl; and, stereoisomer (2R,3R) cannot have             R₉=2-bromoallyl and R₁₃=tert-butyldimethylsilyl

In one embodiment, the present invention provides a process for preparing a compound of formula P. Such a process can be performed, for example, by contacting a compound of formula O under conditions suitable to form a compound of formula P, as set forth below:

In the scheme shown above, R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₉ and R₁₃ are each independently hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, and hydroxyl protecting group, with the proviso that stereoisomer (1S,4R,5R,6R) cannot have R₉=hydrogen and R₁₃=tert-butyldimethylsilyl; and, stereoisomer (1S,4R,5R,6R) cannot have R₉=hydrogen and R₁₃=tert-butyldiphenylsilyl.

In another embodiment, compound of formula O is the (2R,3R) stereoisomer; R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₉ and R₁₃ are each independently hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, and hydroxyl protecting group.

In still another embodiment, compound of formula O is the (2S,3S) stereoisomer; R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₉ and R₁₃ are each independently hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, and hydroxyl protecting group.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about −100° C. up to about 100° C.

Compound O is typically contacted with an epoxidation reagent in the presence or absence of a transition metal reagent and in the presence or absence of a ligand. Epoxidation reagents contemplated for use include, for example, oxygen, tert-butyl hydroperoxide, meta-chloroperbenzoic acid, dimethyl dioxirane, oxone, sodium hypochlorite, sodium periodate, iodosylbenzene and the like. Transition metal reagents contemplated for use include, for example, titanium tetraisopropoxide, polymer supported cyclopentadienyl titanium trichloride, zirconium tetraethoxide, hafnium tetraisopropoxide, vanadium pentoxide, niobium pentaethoxide, tantalum pentaisopropoxide, manganese (II) trifluoromethanesufonate, iron (III) acetylacetonate, molybdenum hexacarbonyl, ruthenium dichloride tris(triphenylphosphine), cobalt (II) trifluoromethanesulfonate, and the like. Ligands contemplated for use include, for example, (R,R) diethyl tartarate, (S,S) diethyl tartarate, N-ethyl ephedrine, N-methylprolinol, porphyrin, 2,2′-[[(1S,2S)-1,2-diphenyl-1,2-ethanediyl]-bis(nitrilomethylidyne)]bis[6-(1,1-dimethylethyl)-4-methyl-phenol, 2,2′-[[(1R,2R)-1,2-diphenyl-1,2-ethanediyl]-bis(nitrilomethylidyne)]bis[6-(1,1-dimethylethyl)-4-methyl-phenol, 2,2′-[(1R,2R)-1,2-cyclohexanediylbis[(E)-nitrilomethylidyne]]bis[6-(1,1-dimethylethyl)-4-methyl-phenol and the like.

In yet another embodiment of the invention, there are provided compounds having the structure P:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, or aryl; R₉ and R₁₃ are each independently hydrogen,         alkyl, substituted alkyl, alkylcarbonyl, substituted         alkylcarbonyl, aryl, arylcarbonyl, or hydroxyl protecting group;     -   With the proviso that:         -   stereoisomer (1S,4R,5R,6R) cannot have R₉ hydrogen and             R₁₃=tert-butyldimethylsilyl; and, stereoisomer (1S,4R,5R,6R)             cannot have R₉=hydrogen and R₁₃=tert-butyldiphenylsilyl;

Invention compounds having structure P maybe optically pure and include stereoisomer (1R,4S,5S,6S) where R₂=R₅=R₉=hydrogen and R₁₃=tert-butyldimethylsilyl; stereoisomer (1S,4S,5S,6R) where R₂=R₅=R₉=hydrogen and R₁₃=tert-butyldimethylsilyl; stereoisomer (1R,4R,5R,6S) where R₂==R₉=hydrogen and R₁₃=tert-butyldimethylsilyl; stereoisomer (1R,4S,5R,6S) where R₂=R₅=R₉=hydrogen and R₁₃=tert-butyldimethylsilyl; stereoisomer (1S,4R,5S,6R) where R₂=R₅=R₉=hydrogen and R₁₃=tert-butyldimethylsilyl; stereoisomer (1S,4S,5R,6R) where R₂=R₅=R₉=hydrogen and R₁₃=tert-butyldimethylsilyl; stereoisomer (1R,4R,5S,6S) where R₂=R₅=R₉=hydrogen and R₁₃=tert-butyldimethylsilyl.

In one embodiment, the present invention provides a process for preparing a compound of formula Q. Such a process can be performed, for example, by contacting a compound of formula P with a nucleophile under conditions suitable to form a compound of formula Q, as set forth below:

In the scheme shown above, R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or hydroxyl protecting group. R₁₃ is alkyl, substituted alkyl and aryl, alkylcarbonyl, substituted alkylcarbonyl, arylcarbonyl, or hydroxyl protecting group. R₁₄ is hydrogen, halogen, alkyl, substituted alkyl, aryl, heteroaryl, saturated heteroaryl, cyano, azido, amino, alkylamino, arylamino, hydrazine, alkylhydrazino, arylhydrazino, alkylcarbonylhydrazino, arylcarbonylhydrazino, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylcarboxy, arylcarboxy, N-protected amino acid, 0protected amino acid, or a solid support; and R₁₅ is hydrogen. In another embodiment, R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or hydroxyl protecting group. R₁₃ is alkyl, substituted alkyl and aryl, alkylcarbonyl, substituted alkylcarbonyl, arylcarbonyl, or hydroxyl protecting group, R₁₄ is hydrogen; and R₁₅ is hydrogen. In still another embodiment, R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or hydroxyl protecting group. R₁₃ is alkyl, substituted alkyl and aryl, alkylcarbonyl, substituted alkylcarbonyl, arylcarbonyl, or hydroxyl protecting group, R₁₄ is fluorine, chlorine, bromine or iodine, and R₁₅ is hydrogen. In yet another embodiment, R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or hydroxyl protecting group. R₁₃ is alkyl, substituted alkyl and aryl, alkylcarbonyl, substituted alkylcarbonyl, arylcarbonyl, or hydroxyl protecting group, R₁₄ is cyano; and R₁₅ is hydrogen, trimethylsilyl, or tert-butyldimethylsilyl.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about −100° C. up to about 150° C.

Compound P is typically contacted with a nucleophile in the presence or absence of a Lewis acidic reagent. Nucleophiles contemplated for use include, for example, water, potassium cyanide, trimethylsilyl cyanide, sodium azide, potassium iodide, sodium fluoride, potassium hydroxide, methanol, sodium ethoxide, benzyl alcohol, 3,5-dimethylphenol, sodium phenoxide, ethyl thiol, potassium phenyl thiolate, ammonia, ammonium hydroxide, hydrazine, ethyl hydrazine, phenyl hydrazine, benzoylhydrazine, methylamine, benzylamine, dibutylamine, aniline, 3-methoxyaniline, diphenylamine, sodium amide, Lithium dimethylamide, potassium benzylmethylamide, lithium anilide, hydrazine, potassium hydrizide, methylhydrazine, phenylhydrazine, benzoylhydrazine, acetylhydrazine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, lithium piperidide, potassium morpholinide, phthalimide, maleimide, adenine, guanine, uracil, thymine, cytosine, imidazole, pyrrole, indole, tetrazole, glycine methyl ester, serine tert-butyl ester, valine ethyl ester lithium salt, N-benzylleucine, methyl lithium, ethyl magnesium bromide, phenyl lithium, diethyl zinc, diethyl mercury, trimethyl aluminum, triethyl indium, trimethyl gallium, Merrifield resin, Wang resin, Rink resin, Wang resin lithium salt, compound of formula N and the like. Lewis acidic reagents contemplated for use include, for example, boron trifluoride, boron trifluoride etherate, boron trifluoride tetrahydrofuran complex, boron trifluoride tert-butyl-methyl ether complex, boron trifluoride dibutyl ether complex, boron trifluoride dihydrate, boron trifluoride di-acetic acid complex, boron trifluoride dimethyl sulfide complex, boron trichloride, boron trichloride dimethyl sulfide complex, boron tribromide, boron tribromide dimethyl sulfide complex, boron triiodide, trimethoxyborane, triethoxyborane, trimethylaluminum, triethylaluminum, aluminum trichloride, aluminum trichloride tetrahydrofuran complex, aluminum tribromide, titanium tetrachloride, titanium tetrabromide, titanium iodide, titanium tetraethoxide, titanium tetraisopropoxide, scandium (III) trifluoromethanesulfonate, yttrium (III) trifluoromethanesulfonate, ytterbium (III) trifluoromethanesulfonate, lanthanum (III) trifluoromethanesulfonate, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, zinc (II) trifluoromethanesulfonate, zinc (II) sulfate, magnesium sulfate, lithium perchlorate, copper (II) trifluoromethanesulfonate, copper (II) tetrafluoroborate and the like.

In yet another embodiment of the invention, there are provided compounds having the structure Q:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl,         alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or         hydroxyl protecting group; R₁₃ is —C(O)OR⁸, where R⁸ is selected         from the group consisting of alkyl, substituted alkyl and aryl         and more specifically R₈ is methyl, methoxymethyl,         9-fluorenylmethyl, ethyl, 2,2,2-trichloromethyl,         1,1-dimethyl-2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,         2-(phenylsulfonyl)ethyl, isobutyl, tert-Butyl, vinyl, allyl,         4-nitrophenyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl,         4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl,         2-(methylthiomethoxy)ethyl, 2-dansenylethyl,         2-(4-nitrophenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl,         2-cyano-1-phenylethyl, thiobenzyl, or 4-ethoxy-1-naphthyl; R₁₄         is hydrogen, halogen, alkyl, substituted alkyl, aryl,         heteroaryl, saturated heteroaryl, cyano, azido, amino,         alkylamino, arylamino, hydroxy, alkoxy, aryloxy, alkylthio,         arylthio, alkylcarboxy, arylcarboxy, N-protected amino acid,         O-protected amino acid, or a solid support; and R₁₅ is hydrogen.

In yet another embodiment of the invention, there are provided compounds having the structure Q:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl,         alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or         hydroxyl protecting group; R₁₃=—Si(R⁸)₃, where R₈ is alkyl,         substituted alkyl and aryl and more specifically R₁₃ is         trimethylsillyl, triethylsilyl, triisopropylsilyl,         dimethylisopropylsilyl, diethylisopropylsilyl,         dimethylhexylsilyl, tert-butyldimethylsilyl,         tert-butyidiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl,         triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl,         tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl,         (2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl,         or tert-butoxydiphenylsilyl; R₁₄ is hydrogen, halogen, alkyl,         substituted alkyl, aryl, heteroaryl, saturated heteroaryl,         cyano, azido, amino, alkylamino, arylamino, hydroxy, alkoxy,         aryloxy, alkylthio, arylthio, alkylcarboxy, arylcarboxy,         N-protected amino acid, O-protected amino acid, or a solid         support; and R₁₅ is hydrogen.     -   With the proviso that:         -   stereoisomer (2R,3S,4R) cannot have R₉=benzyl and             R₂=R₁₄=hydrogen and R₁₃=tert-butyidimethylsilyl;             stereoisomer (2R,3S,4R) cannot have R₉=R₂=R₅, R₁₄=hydrogen             and R₁₃=tert-butyldimethylsilyl; stereoisomer (2R,3S,4R)             cannot have R₉=R₂=R₅=R₁₄=hydrogen and             R₁₃=tert-butyldiphenylsilyl; stereoisomer (2R,3S,4S,5S)             cannot have R₂=R₅=R₉=hydrogen and             R₁₃=tert-butyidiphenylsilyl and R₁₄=p-toluenecarboxy;             stereoisomer (2R,3S,4S,5S) cannot have R₂=R₅=R₉=hydrogen and             R₁₃=tert-butyldimethylsilyl and R₁₄=tricholoroacetamide;             and, stereoisomers (2R,3S,4S,5R) and (2S,3R,4R,5S) cannot             have R₂=R₅=R₉=hydrogen and R₁₃=tert-butyldimethylsilyl and             R₁₄=5,6-dichlorobenzimidazole.

In yet another embodiment of the invention, there are provided compounds having the structure Q:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl,         alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or         hydroxyl protecting group; R₁₃ is benzyl, 2-nitrobenzyl,         2-trifluoromethylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl,         4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-phenylbenzyl,         4-acylaminobenzyl, 4-azidobenzyl, 4-(methylsulfinyl)benzyl,         2,4-dimethoxybenzyl, 4-azido-3-chlorobenzyl,         3,4-dimethoxybenzyl, 2,6-dichlorobenzyl, 2,6-difluorobenzyl,         1-pyrenylmethyl, diphenylmethyl, 4,4′-dinitrobenzhydryl,         5-benzosuberyl, triphenylmethyl (trityl),         α-naphthyldiphenylmethyl, (4-methoxyphenyl)-diphenyl-methyl         (MMT), di-(p-methoxyphenyl)-phenylmethyl,         tri-(p-methoxyphenyl)methyl,         4-(4′-bromophenacyloxy)-phenyldiphenylmethyl,         4,4′,4′-tris(4,5-dichlorophthalimidophenyl)methyl,         4,4′,4″-tris(levulinoyloxyphenyl)methyl,         4,4′-dimethoxy-3″-[N-(imidazolylmethyl)]trityl,         4,4′-dimethoxy-3′-[N-(imidazolyiethyl)carbamoyl]trityl,         1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl,         4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4′-dimethoxytrityl,         9-anthryl, 9-(9-phenyl)xanthenyl, or 9-(9-phenyl-10-oxo)anthryl;         R₁₄ is hydrogen, halogen, alkyl, substituted alkyl, aryl,         heteroaryl, saturated heteroaryl, cyano, azido, amino,         alkylamino, arylamino, hydroxy, alkoxy, aryloxy, alkylthio,         arylthio, alkylcarboxy, arylcarboxy, N-protected amino acid,         O-protected amino acid, or a solid support; and R₁₅ is hydrogen.     -   With the proviso that:         -   stereoisomer (2R, 3S, 4S, 5R) cannot have R₂=R₅=hydrogen and             R₉=benzoyl and R₁₃=(4-methoxyphenyl)-diphenyl-methyl and             R₁₄=N-(9H-purin-6-yl)-benzamide; stereoisomer (2R, 3S, 4S,             5R) cannot have R₂=R₅=hydrogen and R₉=benzoyl and             R₁₃=(4-methoxyphenyl)-diphenyl-methyl and             R₁₄=1H-pyrimidine-2,4-dione; stereoisomer (2R, 3S, 4S, 5R)             cannot have R₂=R₅=hydrogen and R₉=benzoyl and             R₁₃=(4-methoxyphenyl)-diphenyl-methyl and             R₁₄=N-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-benzamide;             stereoisomer (2R, 3S, 4S, 5R) cannot have R₂=R₅=hydrogen and             R₉=benzoyl and R₁₃=(4-methoxyphenyl)-diphenyl-methyl and             R₁₄=N,N-dimethyl-N′-(6-oxo-6,9-dihydro-1H-purin-2-yl)-formamidine;             stereoisomer (2R, 3S, 4R) cannot have R₂=R₅=R₉=R₁₄=hydrogen             and R₁₃=triphenylmethyl; stereoisomer (2R, 3S, 4S) cannot             have R₂=R₅=R₉=R₁₄=hydrogen and R₁₃=benzyl; stereoisomers             (2R, 3S, 4R, 5R) and (2R, 3S, 4R, 5S) cannot have             R₂=R₅=R₉=hydrogen and R₁₃=triphenylmethyl and R₁₄=hydroxy;             and, stereoisomer (2R, 3R, 4R) and (2S, 3S, 4S) cannot have             R₂=R₉=R₁₄=hydrogen and R₅=methyl and R₁₃=triphenylmethyl.

In yet another embodiment of the invention, there are provided compounds having the structure Q:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl,         alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or         hydroxyl protecting group; R₁₃ is alkyl, substituted alkyl and         aryl and more specifically R₁₃ is methyl, tert-butyl, allyl,         propargyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl,         2,4-dinitrophenyl, 2,3,5,6-tetrafluoro-4-trifluoromethyl)phenyl,         methoxymethyl, methylthiomethyl,         (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,         p-methoxy-benzyloxymethyl, p-nitrobenzyloxymethyl,         o-nitrobenzyloxymethyl, (4-methoxyphenoxy)methyl,         gualacolmethyl, tert-butoxymethyl, 4-pentenyloxymethyl,         tert-butyidimethylsiloxymethyl, thexyldimethylsiloxymethyl,         tert-butyldiphenylslioxymethyl, 2-methoxyethoxymethyl,         2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl,         2-(trimethylsilyl)ethoxymethyl, methoxymethyl, 1-ethoxyethyl,         1-(2-chloroethoxy)ethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl,         1-methyl-1-ethoxyethyl, 1-methyl-1-benzyloxyethyl,         1-methyl-1-benzyloxy-2-fluoroethyl, 1-methyl-1-phenoxyethyl,         2,2,2-trichloroethyl, 1-dianisyl-2,2,2-trichloroethyl,         1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 2-trimethylsilylethyl,         2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, tetrahydropyranyl,         3-bromotetrahydropyranyl, tetrahydrothiopyranyl,         1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,         4-methoxytetrahydrothlopyranyl, 4-methoxytetrahydropyranyl         S,S-dioxide, 1-(2-chloro-4-methyl)phenyl]4         methoxypiperidin-4-yl,         1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl,         tetrahydrofuranyl, tetrahydrothiofuranyl, R₁₄ is hydrogen,         halogen, alkyl, substituted alkyl, aryl, heteroaryl, saturated         heteroaryl, cyano, azido, amino, alkylamino, arylamino, hydroxy,         alkoxy, aryloxy, alkylthio, arylthio, alkylcarboxy, arylcarboxy,         N-protected amino acid, O-protected amino acid, or a solid         support; and R₁₅ is hydrogen.     -   With the proviso that         -   Compounds of formula Q cannot have R₂=R₅=R₉=hydrogen and             R₁₃=allyl and R₁₄=hydroxy; Compounds of formula Q cannot             have R₂=R₅=hydrogen and R₉=R₁₃=methyl and R₁₄=methoxy;             stereoisomer (2R,3S,4R,5S) cannot have R₂=R₅=hydrogen and             R₉=R₁₃=methyl and R₁₄=methoxy; stereoisomer (2R,3S,4R,5S)             cannot have R₂=R₅=hydrogen and R₉=benzyl and R₁₃=methyl and             R₁₄=hydroxy; stereoisomer (2R,3S,4R,5S) cannot have             R₂=R₅=hydrogen and R₉=benzyl and R₁₃=methyl and R₁₄=methoxy;             stereoisomer (2R,3S,4S,5S) cannot have R₂=R₅=R₉=hydrogen and             R₁₃=methyl and R₁₄=methoxy; stereoisomer (2R, 3S, 4R) cannot             have R₂=R₅=R₁₄=hydrogen and R₉=R₁₃=methyl.

In yet another embodiment of the invention, there are provided compounds having the structure Q:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl,         alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or         hydroxyl protecting group; R₁₃ is —C(O)R⁸, where R⁸ is alkyl,         substituted alkyl, or aryl and more specifically R₈ is hydrogen,         methyl, ethyl, tert-butyl, adamantyl, crotyl, chloromethyl,         dichloromethyl, trichloromethyl, trifluoromethyl, methoxymethyl,         triphenylmethoxymethyl, phenoxymethyl, 4-chlorophenoxymethyl,         phenylmethyl, diphenylmethyl, 4-methoxycrotyl, 3-phenylpropyl,         4-pentenyl, 4-oxopentyl, 4,4-(ethylenedithio)pentyl,         5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy]-4-oxopentyl,         phenyl, 4-methylphenyl, 4-nitrophenyl, 4-fluorophenyl,         4-chlorophenyl, 4-methoxyphenyl, 4-phenylphenyl,         2,4,6-trimethylphenyl, α-naphthyl, benzoyl; R₁₄ is hydrogen,         halogen, alkyl, substituted alkyl, aryl, heteroaryl, saturated         heteroaryl, cyano, azido, amino, alkylamino, arylamino, hydroxy,         alkoxy, aryloxy, alkylthio, arylthio, alkylcarboxy, arylcarboxy,         N-protected amino acid, O-protected amino acid, or a solid         support; and R₁₅ is hydrogen.     -   With the proviso that         -   stereoisomer (2R,3S,4R,5R) cannot have R₂=R₅=R₉=hydrogen and             R₁₃=acetyl and R₁₄=N-acetamido; stereoisomer (2R,3R,4S,5S)             cannot have R₂=R₅=R₉=hydrogen and R₁₃=acetyl and             R₁₄=acetoxy; stereoisomer (2R,3S,4R) cannot have             R₂=R₅=R₁₄=hydrogen and R₉=R₁₃=tert-butylcarbonyl;             stereoisomer (2R,3S,4R) cannot have R₂=R₅=R₉=R₁₄=hydrogen             and R₁₃=1-naphthoyl; stereoisomer (2R,3S,4R) cannot have             R₂=R₅=R₉=R₁₄=hydrogen and R₁₃=2-naphthoyl; stereoisomer             (2R,3S,4R) cannot have R₂=R₅=R₉=R₁₄=hydrogen and             R₁₃=benzoyl; stereoisomer (2R,3S,4R) cannot have             R₂=R₅=R₉=R₁₄=hydrogen and R₁₃=4-methoxybenzoyl; stereoisomer             (2R, 3S, 4S, 5R) cannot have R₂=R₅=R₉=hydrogen and             R₁₃=3,4,5-trihydroxybenzoyl and             R₁₄=(3,4,5-trihydroxyphenyl)carboxy; stereoisomer (2R, 3S,             4R, 5R) cannot have R₂=R₅=R₉=hydrogen and R₁₃=benzoyl and             R₁₄=phenylcarboxy; stereoisomer (2R, 3R, 4R, 5R) cannot have             R₂=R₅=R₉=hydrogen and R₁₃=benzoyl and R₁₄=phenylcarboxy;             stereoisomer (2R, 3S, 4R, 5R) cannot have R₂=R₅=hydrogen and             R₉=R₁₃=benzoyl and R₁₄=phenylcarboxy; stereoisomer (2R, 3S,             4R, 5R) cannot have R₂=R₅=hydrogen and R₉=R₁₃=benzoyl and             R₁₄=hydroxy; compounds of formula Q cannot have             R₂==R₉=hydrogen and R₁₃=3-(3,4,5-trimethoxyphenyl)acryloyl             and R₁₄=hydroxy; compounds of formula Q cannot have             R₂=R₅=R₉=hydrogen and R₁₃=formyl and R₁₄=hydroxy; compounds             of formula Q cannot have R₂=R₅=R₉=hydrogen and             R₁₃=ethylcarbonyl and R₁₄=hydroxy; compounds of formula Q             cannot have R₂=R₅=R₉=hydrogen and R₁₄=hydroxy and             R₁₃=aminomethylcarbonyl; compounds of formula Q cannot have             R₂=R₅=R₉=hydrogen and R₁₄=hydroxy and             R₁₃=10-aminodecylcarbonyl; compounds of formula Q cannot             have R₂=R₅=R₉=hydrogen and R₁₄=hydroxy and             R₁₃=5-aminopentylcarbonyl; compounds of formula Q cannot             have R₂=R₅=R₉=hydrogen and R₁₄=hydroxy and R₁₃=succinoyl;             and, compounds of formula Q cannot have R₂=R₅=R₅=hydrogen             and R₁₃=3,4,5-trihydroxybenzoyl and R₁₄=hydroxy.

In yet another embodiment of the invention, there are provided compounds having the structure Q:

wherein: R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₉, R₁₃, R₁₅ are each independently hydrogen, alkylcarbonyl, substituted alkylcarbonyl, arylcarbonyl, and hydroxyl protecting group, R₁₄ is cyano; R₁₅ is hydrogen, trimethylsilyl, or tert-butyidimethylsilyl.

In yet another embodiment of the invention, there are provided compounds having the structure Q:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₉, R₁₃ and R₁ are each independently hydrogen,         alkyl, substituted alkyl, aryl, alkylcarbonyl, substituted         alkylcarbonyl, arylcarbonyl, bimethylsilyl,         tert-butyidimethylsilyl, and hydroxyl protecting group; R₁₄ is         alkylthio, or arylthio     -   With the proviso that:         -   stereoisomer (2R,3R,4S,5R) and (2R,3R,4S,5S) cannot have             R₂=R₅=hydrogen, R₅=R₁₃=R₁₅=acetyl, and R₁₄=ethylthio;             stereoisomer (2R,3R,4S,5R) and (2R,3R,4S,5S) cannot have             R₂=R₅=hydrogen, R₉=R₁₃=R₁₅=acetyl, and R₁₄=n-propylthio;             stereoisomers (2R,3S,4S,5R) and (2R,3S,4S,5S) cannot have             R₂=R₅=R₉=R₁₃=R₁₅=hydrogen and R₁₄=benzylthio; stereoisomers             (2R,3R,4S,5R) and (2R,3R,4S,5S) cannot have R₂=R₅=hydrogen,             R₉=R₁₃=R₁₅=acetyl, and R₁₄=benzylthio.

In yet another embodiment of the invention, there are provided compounds having the structure Q:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₉ is hydrogen, alkyl, substituted alkyl, aryl,         alkylcarbonyl, substituted alkylcarbonyl, arylcarbonyl,         trimethylsilyl, tert-butyldimethylsilyl, or hydroxyl protecting         group; R₁₃ is alkyl, substituted alkyl, aryl, alkylcarbonyl,         substituted alkylcarbonyl, arylcarbonyl, trimethylsilyl,         tert-butyldimethylsilyl, or hydroxyl protecting group; R₁₄ is         NHR₁₈ where R₁₈ is hydrogen, alkyl, substituted alkyl, aryl,         alkylcarbonyl, substituted alkylcarbonyl, arylcarbonyl, or amino         protecting group; R₁₅ is hydrogen     -   With the proviso that:         -   stereoisomers (2R,3S,4R,5R) cannot have             R₂=R₅=R₉=R₁₅=hydrogen, R₁₃=acetyl, and R₁₄=acetamido;             stereoisomers (2R,3S,4S,5S) and (2R,3R,4R,5S) cannot have             R₂=R₅=R₉=R₁₅=hydrogen, R₁₃=tert-butyltrimethylsilyl, and             R₁₄=trichloroacetamido.

In yet another embodiment of the invention, there are provided compounds having the structure Q:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₉ and R₁₅ are each independently hydrogen,         alkyl, substituted alkyl, aryl, alkylcarbonyl, substituted         alkylcarbonyl, arylcarbonyl, trimethylsilyl,         tert-butyldimethylsilyl, and hydroxyl protecting group; R₁₃ is         alkyl, substituted alkyl, aryl, alkylcarbonyl, substituted         alkylcarbonyl, arylcarbonyl, trimethylsilyl,         tert-butyldimethylsilyl, or hydroxyl protecting group; R₁₄ is         phthalimide, substituted phthalimide, maleimide substituted         maleimide, or NR₁₈R₁₉ where R₁₈ and R₁₉ are each independently         alkyl, substituted alkyl, alkylcarbonyl, substituted         alkylcarbonyl, aryl, arylcarbonyl, heteroaryl, saturated         heteroaryl, and amino protecting group, and R₁₈ and R₁₉ maybe         taken together with the nitrogen to which they are attached         forming a cyclic system containing 3 to 10 carbon atoms with at         least one substituent as defined for a substituted alkyl.     -   With the proviso that:         -   stereoisomer (2R,3R,4R,5S) cannot have R₂, R₅=hydrogen,             R₉=R₁₃=R₁₅=acetyl, and R₁₄=phtalimido; stereoisomer             (2R,3S,4R,5S) cannot have R₂=R₅=R₉=R₁₃=R₁₅=hydrogen, and             R₁₄=dimethylamino hydrogen chloride; stereoisomer             (2R,3S,4R,5S) cannot have R₂=R₅=R₉=R₁₃=R₁₅=hydrogen, and             R₁₄=trimethylaminoiodide; and, stereoisomer (2R,3S,4R,5S)             cannot have R₂=R₅=R₉=R₁₃=R₁₅=hydrogen, and             R₁₄=N,N-(benzyloxycarboxy)methylamino.

Invention compounds having structure Q maybe optically pure and include 6-(tert-butyldimethylsiloxymethyl)-5-hydroxy-4-(trimethylsiloxy)tetrahydropyran-3-carbonitrile; 6-(tert-Butyidimethylsiloxymethyl)-5-hydroxy-4(-tert-butyldimethylsiloxy)-tetrahydropyran-3-carbonitrile; 6-(tert-butyldimethylsiloxymethyl)-5-hydroxy-4(-trimethylsiloxy)-tetrahydropyran-3-carbonitrile; 5-benzyloxy-2-hydroxymethyl-tetrahydropyran-3,4-diol, 5-benzylamino-2-tert-butyldimethylsilanyloxymethyl)-tetrahydropyran-3,4-diol; 2-hydroxymethyl-tetrahydropyran-3,4,5-triol; 6-(tert-butyldimethylsilanyloxymethyl)-5-hydroxy-4-trimethylsilanyloxy-tetrahydro-pyran-3-carbonitrile; 2-(tert-butyldimethylsilanyloxymethyl)-tetrahydropyran-3,5-diol; 5-azido-2-(tert-butyldimethylsilanyloxymethylytetrahydropyran-3,4-diol; 2-(tert-butyldimethylsilanyloxymethyl)-5-(3-methoxyphenylamino)-tetrahydropyran-3,4-diol; 2-hydroxymethyl-5-phenylsulfanyl-tetrahydropyran-3,4-diol

In one embodiment, the present invention provides a process for preparing a compound of formula S. Such a process can be performed, for example, by contacting a compound of formula N with a compound of formula R under conditions suitable to form a compound of formula S, as set forth below:

In the scheme shown above, R₂, R₅, R₁₆ and R₁₇ are each independently hydrogen, alkyl, substituted alkyl, and aryl.

Solvents contemplated for use in the practice of this particular invention process are typically halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 150° C.

Compound N is typically contacted with compound R in the presence of an acidic reagent or a Lewis acidic reagent. Acidic reagents contemplated for use include, for example, formic acid, acetic acid, fumaric acid, phthalic acid, oxalic acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonic acid, Montmorillonite Clay K-10, Montmorillonite Clay KSF, ammonium chloride, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like. Lewis acidic reagents contemplated for use include, for example, boron trifluoride, trimethylsilyl chloride, trimethylsilylbromide, trimethylsilyl iodide, trimethylsilyl trifluoromethylsulfonate, cerium (III) chloride, scandium (III) trifluoromethanesulfonate, yttrium (III) trifluoromethanesulfonate, ytterbium (III) trifluoromethanesulfonate, lanthanum (III) trifluoromethanesulfonate, iron (III) chloride, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, zinc (II) trifluoromethanesulfonate, zinc (II) sulfate, magnesium sulfate, lithium perchlorate, copper (II) trifluoromethanesulfonate, copper (II) tetrafluoroborate.

In yet another embodiment of the invention, there are provided compounds having the structure S:

wherein:

-   -   R₂, R₅, R₁₆ and R₁₇ are each independently hydrogen, alkyl,         substituted alkyl, and aryl.     -   With the proviso that:         -   stereoisomer (4aR,8aS) cannot have R₂=R₅=R₁₆=hydrogen and             R₁₇=phenyl; and, stereoisomer (4aR,8aS) cannot have             R₂=R₁₀=hydrogen, R₅=(4-methoxyphenyl)-diphenylmethoxymethyl             and R₁₇=phenyl

Invention compounds having structure S maybe optically pure and include 2,2-dimethyl-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine); (4aR,8aR)-2,2-dimethyl-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine; (4aS,8aS)-2,2-dimethyl-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine; (4aR,8aS)-2,2-dimethyl-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine; (4aS,8aR)-2,2-dimethyl-4,4a,6,8a-tetrahydropyrano[3,2-d][1,3]dioxine

In one embodiment, the present invention provides a process for preparing a compound of formula T. Such a process can be performed, for example, by contacting a compound of formula S under conditions suitable to form a compound of formula T, as set forth below:

R₂, R₁, R₁₆ and R₁₇ are each independently hydrogen, alkyl, substituted alkyl, and aryl.

-   -   With the proviso that         -   For compound of formula S, stereoisomer (3aR,7aS) cannot             have R₂=R₅=hydrogen and R₁₀=R₁₇=methyl

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about −100° C. up to about 100° C.

Compound S is typically contacted with an epoxidation reagent in the presence or absence of a transition metal reagent, and in the presence or absence of a ligand. Epoxidation reagents contemplated for use include, for example, oxygen, tert-butyl hydroperoxide, meta-chloroperbenzoic acid, dimethyl dioxirane, oxone, sodium hypochlorite, sodium periodate, iodosylbenzene and the like. Transition metal reagents contemplated for use include, for example, titanium tetraisopropoxide, polymer supported cyclopentadienyl titanium trichloride, zirconium tetraethoxide, hafnium tetraisopropoxide, vanadium pentoxide, niobium pentaethoxide, tantalum pentaisopropoxide, manganese (II) trifluoromethanesulfonate, iron (III) acetylacetonate, molybdenum hexacarbonyl, ruthenium dichloride tris(triphenylphosphine), cobalt (II) trifluoromethanesulfonate, and the like. Ligands contemplated for use include, for example, (R,R) diethyl tartarate, (S,S) diethyl tartarate, N-ethyl ephedrine, N-methylprolinol, porphyrin, 2,2′-[[(1S,2S)-1,2-diphenyl-1,2-ethanediyl]-bis(nitrilomethylidyne)]bis[6-(1,1-dimethylethyl)-4-methyl-phenol, 2,2′-[[(1R,2R)-1,2-diphenyl-1,2-ethanediyl]-bis(nitrilomethylidyne)]bis[6-(1,1-dimethylethyl)-4-methyl-phenol, 2,2′-[(1R,2R)-1,2-cyclohexanediylbis[(E)-nitrilomethylidyne]]bis[6-(1,1-dimethylethyl)-4-methyl-phenol and the like.

In yet another embodiment of the invention, there are provided compounds having the structure T:

wherein:

-   -   R₂, R₅, R₁₆ and R₁₇ are each independently hydrogen, alkyl,         substituted alkyl, and aryl;     -   With the proviso that:         -   stereoisomer (1aR,3aR,7aR,7bR) cannot have             R₂=R₅=R₁₆=hydrogen and R₁₇=phenyl; stereoisomer             (1aS,3aR,7aR,7bS) cannot have R₂=R₅=R₁₆=hydrogen and             R₁₇=phenyl; and, stereoisomer (1aR,3aS,7aS,7bR) cannot have             R₂=R₅=R₁₆=hydrogen and R₁₇=phenyl.

In one embodiment, the present invention provides a process for preparing a compound of formula U. Such a process can be performed, for example, by contacting a compound of formula T with a nucleophile under conditions suitable to form a compound of formula U, as set forth below.

R₂, R₅, R₁₆ and R₁₇ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₁₄ is hydrogen, halogen, alkyl, substituted alky, aryl, heteroaryl, saturated heteroaryl, cyano, azido, amino, alkylamino, arylamino, hydrazine, alkylhydrazino, arylhydrazino, alkylcarbonylhydrazino, arylcarbonylhydrazino, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylcarboxy, arylcarboxy, N-protected amino acid, O-protected amino acid, or a solid support; R₁₅ is hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or hydroxyl protecting group.

With the proviso that:

-   -   For compounds of formula T, stereoisomer (1aS,3aR,7aR,7bS)         cannot have R₂=R₅=R₁₆=hydrogen and R₁₇=phenyl

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 150° C.

Compound T is typically contacted with a nucleophile in the presence or absence of a Lewis acidic reagent. Nucleophiles contemplated for use include, for example, water, potassium cyanide, trimethylsilyl cyanide, sodium azide, potassium iodide, sodium fluoride, potassium hydroxide, methanol, sodium ethoxide, benzyl alcohol, 3,5-dimethylphenol, sodium phenoxide, ethyl thiol, potassium phenyl thiolate, ammonia, ammonium hydroxide, hydrazine, ethyl hydrazine, phenyl hydrazine, benzoylhydrazine, methylamine, benzylamine, dibutylamine, aniline, 3-methoxyaniline, diphenylamine, sodium amide, Lithium dimethylamide, potassium benzylmethylamide, lithium anilide, hydrazine, potassium hydrizide, methylhydrazine, phenylhydrazine, benzoylhydrazine, acetylhydrazine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, lithium piperidide, potassium morpholinide, phthalimide, maleimide, adenine, guanine, uracil, thymine, cytosine, imidazole, pyrrole, indole, tetrazole, glycine methyl ester, serine tert-butyl ester, valine ethyl ester lithium salt, N-benzylleucine, methyl lithium, ethyl magnesium bromide, phenyl lithium, diethyl zinc, diethyl mercury, trimethyl aluminum, triethyl indium, trimethyl gallium, Merrifield resin, Wang resin, Rink resin, Wang resin lithium salt, compound of formula N and the like. Lewis acidic reagents contemplated for use include, for example, boron trifluoride, boron trifluoride etherate, boron trifluoride tetrahydrofuran complex, boron trifluoride tert-butyl-methyl ether complex, boron trifluoride dibutyl ether complex, boron trifluoride dihydrate, boron trifluoride di-acetic acid complex, boron trifluoride dimethyl sulfide complex, boron trichloride, boron trichloride dimethyl sulfide complex, boron tribromide, boron tribromide dimethyl sulfide complex, boron triiodide, trimethoxyborane, triethoxyborane, trimethylaluminum, triethylaluminum, aluminum trichloride, aluminum trichloride tetrahydrofuran complex, aluminum tribromide, titanium tetrachloride, titanium tetrabromide, titanium iodide, titanium tetraethoxide, titanium tetraisopropoxide, scandium (III) trifluoromethanesulfonate, yttrium (III) trifluoromethanesulfonate, ytterbium (III) trifluoromethanesulfonate, lanthanum (III) trifluoromethanesulfonate, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, zinc (II) trifluoromethanesulfonate, zinc (II) sulfate, magnesium sulfate, lithium perchlorate, copper (II) trifluoromethanesulfonate, copper (II) tetrafluoroborate and the like.

In yet another embodiment of the invention, there are provided compounds having the structure U:

wherein:

-   -   R₂, R₅, R₁₆ and R₁₇ are each independently hydrogen, alkyl,         substituted alkyl, and aryl; R₁₄ is hydrogen, halogen, alkyl,         substituted alkyl, aryl, heteroaryl, saturated heteroaryl,         cyano, azido, amino, alkylamino, arylamino, hydrazine,         alkylhydrazino, arylhydrazino, alkylcarbonylhydrazino,         arylcarbonylhydrazino, hydroxy, alkoxy, aryloxy, alkylthio,         arylthio, alkylcarboxy, arylcarboxy, N-protected amino acid,         O-protected amino acid, or a solid support; and R₁₅ is hydrogen,         alkyl, substituted alkyl, alkylcarbonyl, substituted         alkylcarbonyl, aryl, arylcarbonyl, or hydroxyl protecting group.     -   With the proviso that         -   if R₁₆ is methyl then R₁₇ cannot be methyl; if R₁₆ is             hydrogen then R₁₇ cannot be phenyl; if             R₂=R₅=R₁₅=R₁₀=hydrogen and R₁₄=hydroxy then R₁₇ cannot be             3-nitrophenyl; if R₂=R₅=R₁₄=R₁₅=R₁₆=hydrogen then R₁₇ cannot             be 4-nitrophenyl; if R₂=R₁₄=R₁₅=R₁₆=hydrogen then R₁₇ cannot             be 4-methoxyphenyl; if R₂=R₅=R₁₆=hydrogen and R₁₄=methoxy             and R₁₅=methyl then R₁₇ cannot be 4-methoxyphenyl; and, if             R₂=R₅=R₁₅=R₁₆=hydrogen and R₁₄=hydroxy then R₁₇ cannot be             4-methoxyphenyl.

In one embodiment, the present invention provides a process for preparing a compound of formula V. Such a process can be performed, for example, by contacting a compound of formula S under conditions suitable to form a compound of formula V, as set forth below:

In the scheme shown above, R₂, R₅, R₁₆ and R₁₇ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, and aryl; R₁₀ and R₁₁ are hydrogen

-   -   With the proviso that:         -   stereoisomer (4aR,8aS) cannot have R₁₆=hydrogen and             R₁₇=phenyl

Solvents contemplated for use in the practice of this particular Invention process are typically water, halogenated solvents, such as dichloromethane and the like, alcoholic solvents, such as for example 2-methyl-2-propanol and the like, ethereal solvents, such as for example tetrahydrofuran and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about −78° C. up to about 60° C.

Compound S is typically contacted with a suitable mixture of an oxidant, a co-oxidant and a ligand. Oxidants contemplated for use include, for example, osmium tetroxide, potassium permanganate, thallium acetate, potassium periodate, silver acetate and the like, co-oxidants contemplated for use include, for example, N-methylmorpholine oxide, trimethylamine oxide, tert-butyl peroxide, iodine, potassium ferricyanide and the like, ligands contemplated for use include, for example, pyridine, quinuclidine, dihydroquinine acetate, dihydroquinidine acetate, dihydroquinine anthraquinone-1,4-diyl diether ((DHQ)₂AQN), dihydroquinine phthalazine-1,4-diyl diether ((DHQ)₂PHAL), dihydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)₂PYR), dihydroquinidine anthraquinone-1,4-diyl diether ((DHQD)₂AQN), dihydroquinidine phthalazine-1,4-diyl diether ((DHQD)₂PHAL), dihydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQD)₂PYR), tetraethyl ammonium hydroxide, tetraethyl ammonium acetate, N,N,N′N′-tetramethylethylene diamine (TMEDA) and the like.

In yet another embodiment of the invention, there are provided compounds having the structure V:

wherein:

-   -   R₂, R₅, R₁₆ and R₁₇ are each independently hydrogen, alkyl,         substituted alkyl, and aryl; R₁₀ and R₁₁ are each independently         hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted         alkylcarbonyl, aryl, arylcarbonyl, and hydroxyl protecting         group;     -   With the proviso that:         -   If R₁₆ is methyl then R₁₇ cannot be methyl; if R₁₆ is             hydrogen then R₁₇ cannot be phenyl; if             R₂=R₅=R₁₀=R₁₁=R₁₆=hydrogen then R₁₇ cannot be 3-nitrophenyl;             if R₂=R₅=R₁₆=hydrogen and R₁₄=hydroxy then R₁₇ cannot be             4-methoxyphenyl; and, if R₂=R₅=R₁₆=hydrogen and             R₁₀=R₁₁=methyl then R₁₇ cannot be 4-methoxyphenyl.

Invention compounds having structure V maybe optically pure and include 2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol; (4aS,7R,8R,8aR)-2,2-dimethyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol; (4aS,7S,8S,8aR)-2,2-dimethyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol; (4aR,7R,8R,8aS)-2,2-dimethyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol; (4aS,7R,8R,8aS)-2,2-dimethyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol; (4aR,7S,8S,8aR)-2,2-dimethyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol; (4aS,7S,8S,8aS)-2,2-dimethyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol; and, (4aR,7R,8R,8aR)-2,2-dimethyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol

In one embodiment, the present invention provides a process for preparing a compound of formula W. Such a process can be performed, for example, by contacting a compound of formula G under conditions suitable to form a compound of formula W, as set forth below:

In the scheme shown above, R₁ is typically alkyl, substituted alkyl, or aryl; R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₃, R₄, R₆, R₇ are either all hydrogen or, of R₃, R₄, R₅, R₇ three are hydrogen and the fourth is alkyl, substituted alkyl, or aryl; R₉ is hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, or hydroxyl protecting group. In another embodiment, R₁ is ethyl, R₂-R₇ and R₉ are hydrogen.

Solvents contemplated for use in the practice of this particular invention process are typically water, ammonia, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol, 1,2-ethanediol, polyethylene glycol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about −100° C. up to about 100° C.

Compound G is typically contacted with a reducing reagent in the presence or absence of an acidic reagent or a Lewis acidic reagent. Reducing reagents contemplated for use include, for example, borane-dimethyl sulfide complex, 9-borabicyclo[3.3.1.]nonane (9-BBN), catechol borane, lithium borohydride, sodium borohydride, sodium borohydride-methanol complex, potassium borohydride, sodium hydroxyborohydride, lithium triethylborohydride, lithium n-butylborohydride, sodium cyanoborohydride, calcium (II) borohydride, lithium aluminum hydride, diisobutylaluminum hydride, n-butyl-diisobutylaluminum hydride, sodium bis-methoxyethoxyaluminum hydride, triethoxysilane, diethoxymethylsilane, lithium hydride, lithium, sodium, hydrogen Ni/B, and the like. Acidic reagents contemplated for use include, for example, acetic acid, methanesulfonic acid, hydrochloric acid, and the like. Lewis acidic reagents contemplated for use include, for example, trimethoxyborane, triethoxyborane, aluminum trichloride, lithium chloride, vanadium trichloride, dicyclopentadienyl titanium dichloride, cesium fluoride, potassium fluoride, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, and the like.

In yet another embodiment of the invention, there are provided compounds having the structure W:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₃, R₄, R₅, R₇ are either all hydrogen or, of         R₃, R₄, R₆, R₇ three are hydrogen and the fourth is alkyl,         substituted alkyl, or aryl; R₉ and R₂₀ are each independently         hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted         alkylcarbonyl, aryl, arylcarbonyl, and hydroxyl protecting group     -   With the proviso that:         -   stereoisomer (2R,3R) cannot have             R₃=R₄=R₅=R₇=R₉=R₂₀=hydrogen; stereoisomer (2R,3R) cannot             have R₃=R₄=R₅=R₇=hydrogen and R₉=R₂₀=benzoyl; stereoisomer             (2R,3R) cannot have R₃=R₄=R₇=R₉=R₂₀=hydrogen and R₆=methyl;             stereoisomer (2R,3R) cannot have R₃=R₄=R₇=hydrogen and             R₅=methyl and R₉=R₂₀=benzoyl; and, if R₂₀=benzyl then R₃,             R₄, R₆, R₇, R₉ cannot be hydrogen

Invention compounds having structure W maybe optically pure and include 2-allyloxy-pent-4-ene-1,3-diol, (2S,3S)-2-allyloxy-pent-4-ene-1,3-diol; (2R,3S)-2-allyloxy-pent-4-ene-1,3-diol; (2S,3R)-2-allyloxy-pent-4-ene-1,3-diol.

In one embodiment, the present invention provides a process for preparing a compound of formula X. Such a process can be performed, for example, by contacting a compound of formula W with a compound of formula R under conditions suitable to form a compound of formula X, as set forth below:

In the scheme shown above, R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₃, R₄, R₆, R₇ are either all hydrogen or, of R₃, R₄, R₆, R₇ three are hydrogen and the fourth is alkyl, substituted alkyl, or aryl; R₁₆ and R₁₇ are each independently hydrogen, alkyl, substituted alkyl, and aryl.

Solvents contemplated for use in the practice of this particular invention process are typically halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 150° C.

Compound W is typically contacted with compound R in the presence of an acidic reagent or a Lewis acidic reagent. Acidic reagents contemplated for use include, for example, formic acid, acetic acid, fumaric acid, phthalic acid, oxalic acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonic acid, Montmorillonite Clay K-10, Montmorillonite Clay KSF, ammonium chloride, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like. Lewis acidic reagents contemplated for use include, for example, boron trifluoride, trimethylsilyl chloride, trimethylsilylbromide, trimethylsilyl iodide, trimethylsilyl trifluoromethylsulfonate, cerium (III) chloride, scandium (III) trifluoromethanesulfonate, yttrium (III) trifluoromethanesulfonate, ytterbium (III) trifluoromethanesulfonate, lanthanum (III) trifluoromethanesulfonate, iron (III) chloride, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, zinc (II) trifluoromethanesulfonate, zinc (II) sulfate, magnesium sulfate, lithium perchlorate, copper (II) trifluoromethanesulfonate, copper (II) tetrafluoroborate.

In yet another embodiment of the invention, there are provided compounds having the structure X:

wherein:

-   -   R₂ and R₅ are each independently hydrogen, alkyl, substituted         alkyl, and aryl; R₃, R₄, R₆, R₇ are either all hydrogen or, of         R₃, R₄, R₆, R₇ three are hydrogen and the fourth is alkyl,         substituted alkyl, and aryl; R₁₆ and R₁₇ are each independently         hydrogen, alkyl, substituted alkyl, and aryl

Invention compounds having structure X maybe optically pure and include 5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane; (5R,6R)-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane; (5S,6S-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane; (5S,6R-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane; (5R,6S)-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane.

In one embodiment, the present invention provides a process for preparing a compound of formula S. Such a process can be performed, for example, by contacting a compound of formula X under conditions suitable to form a compound of formula S, as set forth below:

In the scheme shown above, R₂, R₅, R₁₆ and R₁₇ are each independently hydrogen, alkyl, substituted alkyl, and aryl. In another embodiment, R₂-R₇ are hydrogen and R₁₆ and R₁₇ are methyl; In still another embodiment, R₂, R₃, R₄, R₅, R₇ are hydrogen, and R₅, R₁₆, R₁₇ are methyl; in yet another embodiment, R₂, R₃, R₄, R₅, R₇ are hydrogen, R₆ is phenyl, and R₁₆-R₁₇ are methyl.

In one embodiment, the present invention provides a process for preparing compound of formula S as a mixture of stereoisomers, such as for example, cis or trans stereoisomers and the like. In another embodiment, the invention provides a process for separating such stereoisomers, such as for example, chromatography, crystallization, re-crystallization, distillation and the like. In still another embodiment, the invention provides a process for preparing compound S as an optically pure isomer.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 150° C.

Compound X is typically contacted with a ring-closing metathesis catalyst. Ring-closing metathesis catalysts contemplated for use include, for example, 2,6-diisopropylphenylimidoneophylidene molybdenum (IV) bis-(tert-butoxide), 2,6-diisopropylphenylimidoneophylidene molybdenum (IV) bis-(hexafluoro-tert-butoxide), 2,6-diisopropylphenylimidoneophylidene[racemic-BIPHEN]molybdenum (IV), 2,6-diisopropylphenylimidoneophylidene[(R)-(+)-BIPHEN]molybdenum (IV), 2,6-diisopropylphenylimidoneophylidene[(S)-(−)-BIPHEN]molybdenum (IV), bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, bis-(tricyclohexylphosphine)-3-methyl-2-butenylidene ruthenium (IV) dichloride, bis-(tricyclopentylphosphine)benzylidine ruthenium (IV) dichloride, bis-(tricyclopentylphosphine)-3-methyl-2-butenylidene ruthenium (IV) dichloride, tricyclohexylphosphine-(1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)-benzylidine ruthenium (IV) dichloride, tricyclohexylphosphine-(1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene)benzylidine ruthenium (IV) dichloride, (1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)-2-isopropoxyphenylmethylene ruthenium (IV) dichloride, (tricyclopentylphosphine)-2-isopropoxyphenylmethylene ruthenium (IV) dichloride, (tricyclopentylphosphine)-2-methoxy-3-naphthylmethylene ruthenium (IV) dichloride and the like.

In one embodiment, the present invention provides a process for preparing a compound of formula P. Such a process can be performed, for example, by contacting a compound of formula Y under conditions suitable to form a compound of formula P, as set forth below:

In the scheme shown above, R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₉ and R₁₃ are each independently hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, and hydroxyl protecting group.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 40° C.

Compound Y is typically contacted with a resolving enzyme in the presence of an acylating agent. Resolving enzymes contemplated for use include lipase, esterase, peptidase, acylase or protease enzymes of mammalian, plant, fungal or bacterial origin, such as for example, Lipase Amano lipase PS-D (immobilized lipase from Pseudomonas cepacia), Amano Lipase PS-C (immobilized lipase from Pseudomonas cepacia), Roche Chirazyme L-3 (lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, carrier-fixed, carrier 2, lyophilizate, from Candida rugosa), Roche Chirazyme L-5 (lipase, solution, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, lyophilizate, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, carrier-fixed, carrier 1, lyophilizate, from Candida antartica, type A), Roche Chirazyme L-10 (lipase, lyophilizate, from Alcaligenes sp.), Altus Biologics 8 (lipase from Mucor miehei) and Altus Biologics 27 (lipase from Alcaligenes sp.) and the like. Acylating agents contemplated for use include, for example, ethyl acetate, vinyl acetate, vinyl propionate, vinyl butyrate, Isopropenyl acetate, 1-ethoxyvinyl acetate, trichloroethyl butyrate, trifluoroethyl butyrate, trifluoroethyl laureate, S-ethyl thiooctanoate, biacetyl monooxime acetate, acetic anhydride, succinic anhydride, amino acid, diketene and the like.

Compound Y can also be contacted with an electrophilic reagent. Electrophilic reagents contemplated for use include, for example, diazomethane, trimethylsilyidiazomethane, alkyl halides, such as for example methyl iodide, benzyl bromide and the like, alkyl triflates, such as for example methyl triflate and the like, alkyl sulfonates, such as for example ethyl toluenesulfonate, butyl methanesulfonate and the like, acyl halides, such as for example acetyl chloride, benzoyl bromide and the like, acid anhydrides, such as for example acetic anhydride, succininc anhydride, maleic anhydride and the like, isocyanates, such as for example methyl isocyanate, phenylisocyanate and the like, chloroformates, such as for example methyl chloroformate, ethyl chloroformate, benzyl chloroformate and the like, sulfonyl halides, such as for example methanesulfonyl chloride, p-tolunesulfonyl chloride and the like, silyl halides, such as for example trimethylsilyl chloride, tertbutyidimethyl silyll chloride and the like, phosphoryl halide such as for example dimethyl chlorophosphate and the like, alpha-beta-unsaturated carbonyl such as for example acrolein, methyl vinyl ketone, cinnamaldehyde and the like.

Compound Y can also be contacted with an alcohol in the presence of an azodicarboxylate and a phosphine base, or any suitable mixtures thereof. Azodicarboxylates contemplated for use include, for example, diethyl azodicarboxylate, dicyclohexyl azodicarboxylate, diisopropyl azodicarboxylate and the like. Phosphine bases contemplated for use include, for example, triethylphosphine, tricyclopentylphosphine, tricyclohexylphosphine, triphenylphosphine, tri-o-tolylphosphine, and the like.

Compound Y can also be contacted with a carboxylic acid or an amino acid in the presence of a coupling agent and a base, or any suitable mixtures thereof. Coupling agents contemplated for use include, for example, dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDCl), N-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 4-nitrophenol, pentafluorophenol, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), O-benzotriazole-N,N,N′N′-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy-tris-dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate, bromo-trispyrrolidino-phosphonium hexafluorophosphate, 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), tetramethylfluoroformamidinium hexafluorophosphate and the like. Bases contemplated for use include, for example, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like.

In another embodiment, the invention provides a process for separating compound of formula P, such as for example, chromatography, crystallization, re-crystallization, distillation and the like.

In one embodiment, the present invention provides a process for preparing a compound of formula P. Such a process can be performed, for example, by contacting a compound of formula Z under conditions suitable to form a compound of formula P, as set forth below:

In the scheme shown above, R₂ and R₅ are each independently hydrogen, alkyl, substituted alkyl, and aryl; R₉ and R₁₃ are each independently hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl, and hydroxyl protecting group.

Solvents contemplated for use in the practice of this particular invention process are typically water, halogenated solvents, such as for example, dichloromethane, dichloroethane and the like, ethereal solvents, such as for example, diethyl ether, dioxane, tetrahydrofuran and the like, polar non-protic solvents, such as for example, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, alcoholic solvents, such as for example, methanol, ethanol, Isopropanol and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about 0° C. up to about 40° C.

Compound Z is typically contacted with a resolving enzyme in the presence of an acylating agent. Resolving enzymes contemplated for use include lipase, esterase, peptidase, acylase or protease enzymes of mammalian, plant, fungal or bacterial origin, such as for example, Lipase Amano lipase PS-D (immobilized lipase from Pseudomonas cepacia), Amano Lipase PS-C (immobilized lipase from Pseudomonas cepacia), Roche Chirazyme L-3 (lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, carrier-fixed, carrier 2, lyophilizate, from Candida rugosa), Roche Chirazyme L-5 (lipase, solution, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, lyophilizate, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, carrier-fixed, carrier 1, lyophilizate, from Candida antartica, type A), Roche Chirazyme L-10 (lipase, lyophilizate, from Alcaligenes sp.), Altus Biologics 8 (lipase from Mucor miehei) and Altus Biologics 27 (lipase from Alcaligenes sp.) and the like. Acylating agents contemplated for use include, for example, ethyl acetate, vinyl acetate, vinyl propionate, vinyl butyrate, isopropenyl acetate, 1-ethoxyvinyl acetate, trichloroethyl butyrate, trifluoroethyl butyrate, trifluoroethyl laureate, S-ethyl thiooctanoate, biacetyl monooxime acetate, acetic anhydride, succinic anhydride, amino acid, diketene and the like.

Compound Z can also be contacted with an electrophilic reagent Electrophilic reagents contemplated for use include, for example, diazomethane, trimethylsilyldiazomethane, alkyl halides, such as for example methyl iodide, benzyl bromide and the like, alkyl triflates, such as for example methyl triflate and the like, alkyl sulfonates, such as for example ethyl toluenesulfonate, butyl methanesulfonate and the like, acyl halides, such as for example acetyl chloride, benzoyl bromide and the like, acid anhydrides, such as for example acetic anhydride, succininc anhydride, maleic anhydride and the like, isocyanates, such as for example methyl isocyanate, phenylisocyanate and the like, chloroformates, such as for example methyl chloroformate, ethyl chloroformate, benzyl chloroformate and the like, sulfonyl halides, such as for example methanesulfonyl chloride, p-tolunesulfonyl chloride and the like, silyl halides, such as for example trimethylsilyl chloride, tertbutyidimethyl silyll chloride and the like, phosphoryl halide such as for example dimethyl chlorophosphate and the like, alpha-beta-unsaturated carbonyl such as for example acrolein, methyl vinyl ketone, cinnamaldehyde and the like.

Compound Z can also be contacted with an alcohol in the presence of an azodicarboxylate and a phosphine base, or any suitable mixtures thereof. Azodicarboxylates contemplated for use include, for example, diethyl azodicarboxylate, dicyclohexyl azodicarboxylate, diisopropyl azodicarboxylate and the like. Phosphine bases contemplated for use include, for example, triethylphosphine, tricyclopentylphosphine, tricyclohexylphosphine, triphenylphosphine, tri-o-tolylphosphine, and the like.

Compound Z can also be contacted with a carboxylic acid or an amino acid in the presence of a coupling agent and a base, or any suitable mixtures thereof. Coupling agents contemplated for use include, for example, dicyclohexylcarbodiimide (DCC), diisopropyl carbodiiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDCl), N-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 4-nitrophenol, pentafluorophenol, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), O-benzotriazole-N,N,N′N′-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy-tris-dimethylaminoyphosphonium hexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate, bromo-trispyrrolidino-phosphonium hexafluorophosphate, 2-(5-norbornene-2,3-dicarboximido)-1,3,3-tetramethyluronium tetrafluoroborate (TNTU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), tetramethylfluoroformamidinium hexafluorophosphate and the like. Bases contemplated for use include, for example, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like.

In another embodiment, the invention provides a process for separating compound of formula P, such as for example, chromatography, crystallization, re-crystallization, distillation and the like.

General Methods of Preparation

Used herein, the following abbreviations have the following meanings: Me refers to methyl (CH₃—), Et refers to ethyl (CH₃CH₂—), i-Pr refers to isopropyl ((CH₃)₂CH₂—), t-Bu or tert-butyl refers to tertiary butyl ((CH₃)₃CH—), Ph refers to phenyl, Bn refers to benzyl (PhCH₂—), Bz refers to benzoyl (PhCO—), MOM refers to methoxymethyl, Ac refers to acetyl, TMS refers to trimethylsilyl, TBS refers to ter-butyldimethylsilyl, Ms refers to methanesulfonyl (CH₃SO₂—), Ts refers to p-toluenesulfonyl (p-CH₃PhSO₂—), Tf refers to trifluoromethanesulfonyl (CF₃SO₂—), TfO refers to trifluoromethanesulfonate (CF₃SO₃—), DMF refers to N,N-dimethylformamide, DCM refers to dichloromethane (CH₂Cl₂), THF refers to tetrahydrofuran, EtOAc refers to ethyl acetate, Et₂O refers to diethyl ether, MeCN refers to acetonitrile (CH₃CN), NMP refers to 1-N-methyl-2-pyrrolidinone, DMA refers to N,N-dimethylacetamide, DMSO refers to dimethylsulfoxide, DCC refers to 1,3-dicyclohexyldicarbodiimide, EDCl refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, Boc refers to tert-butylcarbonyl, Fmoc refers to 9-fluorenylmethoxycarbonyl, TBAF refers to tetrabutylammonium fluoride, TBAI refers to tetrabutylammonium iodide, TMEDA refers to N,N,N,N-tetramethylethylene diamine, Dess-Martin periodinane or Dess Martin reagent refers to 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, DMAP refers to 4-N,N-dimethylaminopyridine, (i-Pr)₂NEt or DIEA or Hunig's base refers to N,N-diethylisopropylamine, DBU refers to 1,8-Diazabicyclo[5.4.0]undec-7-ene, (DHQ)₂AQN refers to dihydroquinine anthraquinone-1,4-diyl diether, (DHQ)₂PHAL refers to dihydroquinine phthalazine-1,4-diyl diether, (DHQ)₂PYR refers to dihydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQD)₂AQN refers to dihydroquinidine anthraquinone-1,4-diyl diether, (DHQD)₂PHAL refers to dihydroquinidine phthalazine-1,4-diyl diether, (DHQD)₂PYR refers to dihydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether, LDA refers to lithium diisopropylamide, LiTMP refers to lithium 2,2,6,6-tetramethylpiperdinamide, n-BuLi refers to n-butyllithium, t-BuLi refers to tert-butyl lithium, IBA refers to 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, OSO₄ refers to osmium tetroxide, m-CPBA refers to meta-chloroperbenzoic acid, DMD refers to dimethyl dioxirane, PDC refers to pyridinium dichromate, NMO refers to N-methyl morpholine-N-oxide, NaHMDS refers to sodium hexamethyldisilazide, LiHMDS refers to lithium hexamethyldisilazide, HMPA refers to hexamethylphosphoramide, TMSCl refers to trimethylsilyl chloride, TMSCN refers to trimethylsilyl cyanide, TBSCl refers to tert-butyidimethylsilyl chloride, TFA refers to trifluoroacetic acid, TFM refers to trifluoroacetic anhydride, AcOH refers to acetic acid, Ac₂O refers to acetic anhydride, AcCl refers to acetyl chloride, TsOH refers to p-toluenesulfonic acid, TsCl refer to p-toluenesulfonyl chloride, MBHA refers to 4-methylbenzhydrylamine, BHA refers to benzhydrylamine, ZnCl₂ refers to zinc (II) dichloride, BF₃ refers to boron trifluoride, Y(OTf)₂ refers to yttrium (III) trifluoromethanesulfonate, Cu(BF₄)₂ refers to copper (II) tetrafluoroborate, LAH refers to lithium aluminum hydride (LiAlH₄), NaHCO₃ refers to sodium bicarbonate, K₂CO₃ refers to potassium carbonate, NaOH refers to sodium hydroxide, KOH refers to potassium hydroxide, LiOH refers to lithium hydroxide, HCl refers to hydrochloric acid, H₂SO₄ refers to sulfuric acid, MgSO₄ refers to magnesium sulfate, and Na₂SO₄ refers to sodium sulfate. 1H NMR refers to proton nuclear magnetic resonance, 13C NMR refers to carbon 13 nuclear magnetic resonance, NOE refers to nuclear overhauser effect, NOESY refers to nuclear overhauser and exchange spectroscopy, COSY refers to homonuclear correlation spectroscopy, HMQC refers to proton detected heteronuclear multiplet-quantum coherence, HMBC refers to heteronuclear multiple-bond connectivity, s refers to singlet, br s refers to broad singlet, d refers to doublet, br d refers to broad doublet, t refers to triplet, q refers to quartet, dd refers to double doublet, m refers to multiplet, ppm refers to parts per million, IR refers to infrared spectrometry, MS refers to mass spectrometry, HRMS refers to high resolution mass spectrometry, EI refers to electron impact, FAB refers to fast atom bombardment, CI refers to chemical ionization, HPLC refers to high pressure liquid chromatography, TLC refer to thin layer chromatography, R_(f) refers to, R_(t) refers to retention time, GC refers to gas chromatography, min is minutes, h is hours, rt or RT is room temperature, g is grams, mg is milligrams, L is liters, mL is milliliters, mol is moles and mmol is millimoles.

For all of the following examples, standard work-up and purification methods can be utilized and will be obvious to those skilled in the art. Synthetic methodologies that make up the invention are shown in Schemes 1-10. These Schemes are intended to describe the applicable chemistry through the use of specific examples and are not indicative of the scope of the invention.

EXAMPLES

The following non-limiting examples illustrate the inventors' preferred methods for carrying out the process of the invention.

Example 1 Preparation of Allyloxy-Acetic Acid Ethyl Ester

A round-bottom flask was charged with NaH (1.76 g, 44 mmol, 60% dispersion in mineral oil) and flushed with argon. Hexane (10 ml×2) was added and decanted. DMF (10 ml) was added into the flask and the resulting solution was cooled to 0° C. Ethyl glycolate (4.16 g, 40.0 mmol) was added over 10 min. The solution was allowed to gradually warm to 25° C. and was maintained at that temperature for 2H. The solution was cooled to 0° C. and allyl bromide (5.32 g, 44.0 mmol) was added over 10 min. The solution was allowed to gradually warm to 25° C. and stirred at that temperature for 2 h. Aqueous solution NH₄Cl (10 ml) was added to the reaction and the mixture was diluted with EtOAc (60 ml). The organic layer was separated and washed with H₂O (20 ml×2), dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by distillation under reduced pressure

Yield=4.29 g, 75%; colorless liquid; bp=38-39° C., 2 mmHg;

IR (neat): 1985, 1756, 1724, 1203, 1130 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 5.90-5.70 (m, 1H), 5.25-5.00 (m, 2H), 4.10-4.20 (m, 2H), 3.92-4.05 (m, 4H), 1.21 (t, J=7 Hz, 3H);

¹³C NMR (CDCl₃, 100 MHz) δ 170.09 (C), 133.62 (CH), 117.78 (CH₂), 72.10 (CH₂), 66.99 (CH₂), 60.53 (CH₂), 13.94 (CH₃);

MS (m/z, relative intensity): 144 (M⁺, 14), 115 (22), 103 (100), 83 (85); HRMS: calculated for C₇H₁₂O₃ (M⁺): 144.0786; found 144.0783.

Example 2 Preparation of 2-allyloxy-3-hydroxypent-4-enoic acid ethyl ester

Under an atmosphere of argon, n-BuLi (3 mmol, 1.2 ml, 2.5 M in hexane) was added dropwise to a solution of diisopropylamine (281 mg, 2.78 mmol) in dry THF (20 ml) at −78° C. After stirring for 20-30 min, a solution of allyloxy-acetic acid ethyl ester (200 mg, 1.38 mmol) in THF (4 ml) was added and the mixture was stirred at −78° C. for 10 min. Acrolein (79 mg, 1.38 mmol) was added into the reaction mixture and stirring was maintained until all starting materials were consumed. The reaction was quenched by addition of EtOH (2 ml) and warmed to room temperature. The solution was diluted with EtOAc (60 ml), washed with H₂O (20 ml×2), dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

Yield=961 mg, 82%; colorless liquid; R_(f)=0.25 in 20% EtOAc-hexane)

IR (neat): 3300-3600, 2977, 1742, 1364, 1231, 1134, 1028, 927 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 6.0-5.8 (m, 2H), 5.3-5.1 (m, 4H), 4.44.2 (m, 1H), 4.2-4.0 (m, 3H), 3.9-3.8 (m, 2H), 2.73 (br s, 1H), 1.2 (t, J=7 Hz, 3H);

¹³C NMR (CDCl₃, 100 MHz, 2:1 isomeric forms, * denotes minor isomer)

170.35* (C), 170.08 (C), 135.77* (CH), 135.42 (CH), 133.56 (CH), 133.47* (CH), 118.23* (CH₂), 118.12 (CH₂), 117.14* (CH₂), 116.96 (CH₂), 80.85 (one CH and one CH*), 73.32* (CH), 72.99 (CH), 71.88* (CH₂), 71.87 (CH₂), 60.99* (CH₂), 60.91 (CH₂), 14.08 (CH₃), 14.05* (CH₃);

MS (m/z, relative intensity): 200 (M⁺, 7), 182 (27), 153 (41), 136 (51), 115 (37), 95 (100);

HRMS calculated for C₁₀H₁₆O₄ (M⁺): 200.1048; found 200.1044.

Example 3 Preparation of 3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

To a solution of 2-allyloxy-3-hydroxypent-4-enoic acid ethyl ester (200 mg, 1.0 mmol) in CH₂Cl₂ (10 ml) was added bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) chloride (20 mg, 0.024 mmol) and the resulting mixture was stirred at ambient temperature for 4H. Bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) chloride (20 mg, 0.024 mmol) was added again and the resulting mixture was stirred at ambient temperature for an additional 10 h. The solution was concentrated in vacuo. The crude product was purified by flash chromatography with 25 to 30% EtOAc-hexane

trans 3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=84 mg (49%); R_(f)=0.29 in 40% EtOAc-hexane

IR (neat): 3200-3600, 2976, 1747, 1185, 1111, 1024 cm⁻¹; ¹H NMR (CDC₃, 400 MHz) δ 5.78 (br s, 2H), 4.10-4.35 (m, 5H), 3.93 (d, J=7 Hz, 1H), 3.07 (br s, 1H), 1.24 (t, J=7 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 170.58 (C), 127.49 (CH), 126.54 (CH), 77.00 (CH), 64.98 (CH₂), 64.32 (CH), 61.53 (CH₂), 14.00 (CH₃); MS (m/z, relative intensity): 172 (M⁺, 2), 141 (6), 112 (16), 81 (100); HRMS calculated for C₈H₁₂O₄ (M⁺): 172.0735; found 172.0730.

cis 3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=69 mg (42%); R_(f)=0.06 in 40% EtOAc-hexane

IR (neat): 3200-3600, 2975, 2926, 2841, 1746, 1642, 1182, 1097 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 6.00-6.15 (m, 1H), 5.90-5.96 (m, 1H), 4.10-4.40 (m, 7H), 1.28 (t, J=7 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 169.07 (C), 130.15 (CH), 125.96 (CH), 77.50 (CH), 66.09 (CH₂), 63.48 (CH), 61.36 (CH₂), 14.21 (CH₃); MS (m/z, relative intensity): 172 (M⁺, 2), 141 (6), 112 (16), 81 (100); exact mass calculated for C₈H₁₂O₄ (M⁺): 172.0735; found 172.0730.

Example 4 Resolution of racemic trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Mucor miehei

Vinyl acetate (200 μl) was added to a suspension of racemic trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (41 mg) and lipase from Mucor miehei (50 mg) in 5 ml of toluene. The mixture was agitated for 18H at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

trans-(2R,3R)-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=22 mg (43%); optical purity: >99.9% ee; Colorless liquid; R_(f)=0.64 in 40% EtOAc-hexane;

¹H NMR (CDCl₃ 400 MHz) δ 5.96 (dd, J=10.4, 1.0 Hz, 1H), 5.80-5.85 (m, 1H), 5.44 (br s, 1H), 4.40 (dd, J=2.4, 17.3 Hz, 1H), 4.10-4.25 (m, 4H), 2.03 (s, 3H), 1.23 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 170.25 (C), 168.87 (C), 130.63 (CH), 122.00 (CH), 74.49 (CH), 65.33 (CH), 63.63 (CH₂), 61.50 (CH₂), 20.96 (CH₃), 14.02 (CH₃);

cis-(2S,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=17 mg (42%); optical purity: 89% ee; Colorless liquid, R_(f)=0.39 in 40% EtOAc-hexane. IR (neat): 3200-3600, 2976, 1747, 1185, 1111, 1024 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 5.78 (br s, 2H), 4.10-4.35 (m, 5H), 3.93 (d, J=7 Hz, 1H), 3.07 (br s, 1H), 1.24 (t, J=7 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 170.58 (C), 127.49 (CH), 126.54 (CH), 77.00 (CH), 64.98 (CH₂), 64.32 (CH), 61.53 (CH₂), 14.00 (CH₃);

HRMS calculated for C₈H₁₂O₄ (M⁺): 172.0735; found 172.0733.

Example 5 Resolution of racemic trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Alcaligenes sp.

Vinyl acetate (200 μl) was added to a suspension of racemic trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (53 mg) and immobilized lipase from Alcaligenes sp. (50 mg) in 5 ml of toluene. The mixture was agitated for 14H at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

trans-(2R,3R)-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=32 mg (49%); optical purity: >95% ee;

trans-2S,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=25 mg (47%); optical purity: >99.9% ee;

Example 6 Resolution of racemic trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Candida antartica, type A

Vinyl acetate (10 μl) was added to a suspension of racemic trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (5 mg) and lipase from Candida antartica, type A (11 mg) in 1 ml of toluene. The mixture was agitated for 24H at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

trans-(2R,3R)-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

trans-(2S,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: 88% ee;

Example 7 Resolution of racemic trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Alcaligenes sp.

Vinyl acetate (10 μl) was added to a suspension of racemic trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (5 mg) and lipase from Alcaligenes sp. (11 mg) in 1 ml of toluene. The mixture was agitated for 24H at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

trans-(2R,3R)-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

trans-(2S,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: 98.8% ee;

Example 8 Resolution of racemic trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Pseudomonas cepacia

Vinyl acetate (10 μl) was added to a suspension of racemic trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (6 mg) and lipase from Pseudomonas cepacia (12 mg) in 1 ml of toluene. The mixture was agitated for 4H at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

trans-(2R,3R-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

trans-(2S,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: 99.4% ee;

Example 9 Resolution of racemic cis-3-hydroxy-3,6-dlhydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Mucor miehei

Vinyl acetate (200 μl) was added to a suspension of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (42 mg) and lipase from Mucor miehei (53 mg) in 5 ml of toluene. The mixture was agitated for 18H at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

cis-(2S,3R)-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=24 mg (44%); optical purity: >99.9% ee; Colorless liquid; R_(f)=0.34 in 70% EtOAc-hexane;

IR (neat): 2980, 2932, 2831, 1738, 1375, 1234, 1105, 1023 cm¹;

¹H NMR (CDCl₃, 400 MHz) δ 5.95-6.10 (m, 2H), 5.30-5.35 (m, 1H), 4.41 (dd, J=3.4, 1.6 Hz, 1H), 4.15-4.40 (m, 4H), 2.00 (s, 3H), 1.25 (t, J=7.2 Hz, 3H);

¹³C NMR (CDCl₃, 100 MHz) δ 170.12 (C), 167.91 (C), 132.06 (CH), 121.72 (CH), 75.12 (CH), 65.77 (CH₂), 64.87 (CH), 61.33 (CH₂), 20.67 (CH₃), 14.14 (CH₃);

MS (m/z, relative intensity): 215 (M⁺+1, 6), 213 (M⁺−1, 18), 153 (100), 149 (30);

HRMS calculated for C₁₀H₁₄O₅ (M⁺): 214.0841; found 214.0839.

cis-(2R,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=20 mg (48%); optical purity: 89% ee; Colorless liquid; R_(f)=0.61 in 70% EtOAc-hexane;

IR (neat): 3200-3600, 2975, 2926, 2841, 1746, 1642, 1182, 1097 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 6.00-6.15 (m, 1H), 5.90-5.96 (m, 1H), 4.10-4.40 (m, 7H), 1.28 (t, J=7 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 169.07 (C), 130.15 (CH), 125.96 (CH), 77.50 (CH), 66.09 (CH₂), 63.48 (CH), 61.36 (CH₂), 14.21 (CH₃);

MS (m/z, relative intensity): 172 (M⁺, 2), 141 (6), 112 (16), 81 (100); exact mass calculated for C₈H₁₂O₄ (M⁺): 172.0735; found 172.0730.

Example 10 Resolution of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Alcaligenes sp.

Vinyl acetate (200 μl) was added to a suspension of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (57 mg) and lipase from Alcaligenes sp. (51 mg) in 5 ml of toluene. The mixture was agitated for 14H at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

cis-(2S,3R)-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=32 mg (49%); optical purity: 98.8% ee;

cis-(2R,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=27 mg (48%); optical purity: >99.9% ee;

Example 11 Resolution of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Candida Rugosa

Vinyl acetate (10 μl) was added to a suspension of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (4 mg) and lipase from Candida Rugosa (20 mg) in 1 ml of toluene. The mixture was agitated for 34H at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

cis-(2S,3R)-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

cis-(2R,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

Example 12 Resolution of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Candida antartica, type A

Vinyl acetate (10 μl) was added to a suspension of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (4 mg) and lipase from Candida antartica, type A (11 mg) in 1 ml of toluene. The mixture was agitated for 20 h at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

cis-(2S,3R)-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

cis-(2R,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

Example 13 Resolution of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Pseudomonas cepacia

Vinyl acetate (10 μl) was added to a suspension of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (4 mg) and lipase from Pseudomonas cepacia (9 mg) in 1 ml of toluene. The mixture was agitated for 4H at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

cis-(2S,3R)-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

cis-(2R,3S-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

Example 14 Resolution of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester using lipase from Pseudomonas fluorescens

Vinyl acetate (10 μl) was added to a suspension of racemic cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (4 mg) and lipase from Pseudomonas fluorescens (10 mg) in 1 ml of toluene. The mixture was agitated for 38H at ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.

cis-(2S,3R)-3-Acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

cis-(2R,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

optical purity: >99.5% ee;

Example 15 Preparation of (2R,3R,4S,5S) and (2R,3R,4R,5R)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl esters

To (2R,3R)-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (300 mg, 1.40 mmol) in 27 ml of THF-tert-BuOH—H₂O (6:17.7:3 ml) was added NMO (612 mg, 4.47 mmol) and the solution was stirred for 5 min at ambient temperature. OsO₄ (0.3 ml, 2.5 wt % in tert-BuOH) was added and the mixture was stirred at ambient temperature for 72H. Sodium hydrosulphite (1.2 g), Florisil (12.0 g) and H₂O (10 ml) were added sequentially and the mixture was stirred for 30 min, washed with acetone (500 ml), filtered through filter paper and extracted with EtOAc (2×300 ml) in vacuo. The crude product was purified by flash chromatography with 90% EtOAc-hexane to give (2R,3R,4S,5S)- and (2R,3R,4R,5R)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl esters in 60% yield.

(2R,3R,4R,5R)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester

Colorless oil; Yield: 10%; R_(f)=0.53 in EtOAc

IR (neat): 3600-3200, 2952, 2925, 2868, 1738, 1458, 1375, 1242, 1039 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 4.83-4.90 (m, 1H), 4.22-4.32 (m, 3H), 4.15 (d, J=9.0 Hz, 1H), 3.80-3.90 (m, 2H), 3.74 (dd, J=10.1, 10.8 Hz, 1H), 2.09 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 171.29 (C), 170.28 (C), 74.48 (CH), 69.44 (CH), 68.85 (CH), 67.39 (CH), 63.23 (CH₂), 62.32 (CH₂), 21.29 (CH₃), 14.48 (CH₃); EIMS (m/z, relative intensity): 248 (M⁺, 2), 206 (4), 145 (30), 97 (20), 57 (38), 43 (100).

(2R,3R,4S,5S)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester

Colorless liquid, Yield: 50%; R_(f)=0.5 in EtOAc

IR (neat): 3640-3080, 2983, 1739, 1375, 1242, 1107, 1050 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 5.20 (dd, J=8.4, 8.4 Hz, 1H), 4.08-4.20 (m, 3H), 3.98 (d, J=1.7 Hz, 1H), 3.84 (d, J=8.3 Hz, 1H), 3.75 (d, J=8.4 Hz, 1H), 3.58 (dd, J=10.6, 1.7 Hz, 1H), 3.09 (s, 3H), 2.07 (s, 3H), 1.24 (t, J=7.2 Hz, 3H); ¹³C NMR (CDCl₃, 400 MHz) δ 170.83 (C), 168.48 (C), 75.95 (CH), 71.33 (CH), 70.82 (CH), 68.59 (CH₂), 67.84 (CH), 61.85 (CH₂), 20.85 (CH₂), 13.94 (CH₃); EIMS (m/z, relative intensity): 248 (M⁺, 1), 230 (3), 205 (18), 157 (26), 115 (40), 97 (68), 43 (100); exact mass calculated for C₁₀H₁₆O₇ (M⁺): 248.0896; found 248.0887

X-ray crystal structure of (2R,3R,4S,5S)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester

Example 16 Preparation of (2S,3S,4R,5R) and (2S,3S,4S,5S)-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl esters

To (2S,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (100 mg, 0.58 mmol) in 9 ml of THF-tert-BuOH—H₂O (2:5.9:1) was added NMO (235 mg, 1.72 mmol) and the solution was stirred for 5 min at ambient temperature. OsO₄ (0.1 ml, 2.5 wt % in tert-BuOH) was added and the mixture was stirred at ambient temperature for 24 H. Sodium hydrosulphite (0.4 g), Florisil (4.0 g) and H₂O (10 ml) were sequentially added and the mixture was stirred for 30 minutes, washed with acetone (200 ml), filtered through filter paper and extracted with EtOAc (2×100 ml). The combined organic layers were washed with brine (100 ml), dried over Na₂SO₄, and concentrated in vacuo. The crude product was purified by flash chromatography with 90% EtOAc-hexane to give (2S,3S,4R,5R)- and (2S,3S,4S,5S)-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl esters in 60% yield.

(2S,3S,4R,5R)-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester

Colorless oil; Yield: 50%;

IR (neat): 3640-3080, 2980, 2920, 1732, 1235, 1102, 629 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) 67 4.34 (br s, 3H), 4.21 (q, J=7.2 Hz, 2H), 4.05 (d, J=1.7 Hz, 1H), 4.04 (dd, J=12.6, 1.7 Hz, 1H), 3.90-3.98 (m, 1H), 3.68 (d, J=9.4 Hz, 1H), 3.66-3.60 (m, 1H), 3.55 (d, J=12.2 Hz, 1H), 1.27 (t, J=7.2 Hz, 3H); ¹³C NMR (CDCl₃, 400 MHz) δ 170.30 (C), 78.88 (CH), 73.84 (CH), 70.27 (CH₂), 68.92 (CH), 68.70 (CH), 61.84 (CH₂), 13.99 (CH₃); EIMS (m/z, relative intensity): 207 (M⁺+1, 100), 133 (5), 115 (7), 73 (32), 57 (12); exact mass calculated for C₈H₁₄O₆ (M⁺): 206.0790; found 206.0788.

(2S,3S,4S,5S)-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester

Colorless oil; Yield: 10%;

IR (neat): 3640-3080, 2980, 2926, 1732, 1645, 1381, 1204, 1099, 1043 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 4.22-4.30 (m, 2H), 4.11-4.13 (d, J=8.6 Hz, 1H), 3.70-3.90 (m, 3H), 3.52-3.62 (m, 2H), 1.30 (t, J=7.2 Hz, 3H); EIMS (m/z, relative intensity): 206 (M⁺, 17), 188 (4), 167 (18), 149 (49), 73 (70), 57 (83), 43(100);

Example 17 Preparation of (+)-(2S,3R,4S,5S)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester

To (2S,3R)-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (200 mg, 0.93 mmol) in 18 ml of THF-tert-BuOH—H₂O (4:11.8:2) was added NMO (408 mg, 2.98 mmol) and the solution was stirred for 5 min at ambient temperature. OsO₄ (0.2 ml, 2.5 wt % in tert-BuOH) was added and the solution was stirred at ambient temperature for 72 H. Sodium hydrosulphite (0.83 g), Florisil (2.0 g) and H₂O (2 ml) were added sequentially and the mixture was stirred for 30 minutes, washed with 200 ml EtOAc, filtered through filter paper and the solvent was evaporated. The crude product was purified by flash chromatography with 20-80% EtOAc-hexane to give (2S,3R,4S,5S)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester

Yield: 65%; Colorless oil; R_(f)=0.4 in 100% EtOAc;

IR (neat): 3600-3200, 2923, 2851, 1740, 1483, 1376, 1233, 1121, 1065 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 5.21 (dd, J=1.7 Hz, 3.8 Hz, 1H), 4.45 (d, J=1.7 Hz, 1H), 4.14-4.20 (m, 2H), 4.02-4.04 (m, 1H), 3.81-3.94 (m, 2H), 3.55 (dd, J=10.2, 10.2 Hz, 1H), 3.31 (br s, 2H), 2.02 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); ¹³C NMR (CDC3, 400 MHz) δ 170.13 (C), 168.75 (C), 72.42 (CH), 71.93 (CH), 66.97 (CH), 65.52 (CH₂), 64.08 (CH), 61.63 (CH₂), 20.61 (CH₃), 14.00 (CH₃); EIMS (m/z, relative intensity): 249 (M⁺+1, 5), 206 (8), 175 (10), 157 (39), 115 (37), 43 (100); exact mass calculated for C₁₀H₁₆O₇ (M⁺): 248.0896; found 248.0887.

Example 18 Preparation of (+)-(2R,3S,4R,5R)-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester

To (2R,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (200 mg, 1.16 mmol) in 18 ml THF-tert-BuOH—H₂O (4:11.8:2) was added NMO (408 mg, 3.43 mmol) and the solution was stirred for 5 min at ambient temperature. OsO₄ (0.2 ml, 2.5 wt % in tert-BuOH) was added and the mixture was stirred at ambient temperature for 72 H. Sodium hydrosulphite (0.83 g), Florisil (2.0 g) and H₂O (2 ml) were added sequentially and the mixture was stirred for 30 minutes, washed with 200 ml EtOAc, filtered through filter paper and the solvent was evaporated. The crude product was purified by flash chromatography with 20-80% EtOAc-hexane to give (2R,3S,4R,5R)-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester

Yield=65%; Colorless oil; R_(f)=0.4 in 100% EtOAc;

¹H NMR (CDC₃, 400 MHz) δ 4.36 (s, 1H), 4.18-4.26 (m, 2H), 4.00-4.16 (m, 6H), 3.80-3.90 (m, 1H), 3.48-3.58 (m, 1H), 1.26 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 170.59 (C), 74.20 (CH), 70.75 (CH), 69.69 (CH), 65.56 (CH₂), 64.10 (CH), 61.74 (CH₂), 14.04 (CH₃); EIMS (m/z, relative intensity): 207 (M⁺+1, 11), 206 (19), 133 (23), 115 (61), 73 (85), 57 (80), 43 (100); Exact mass calculated for C₈H₁₄O₆ (M⁺): 206.0790; found 206.0787.

Example 19 Preparation of (2R,3R,4S,5S)-3,5-diacetoxy-4-hydroxy-tetrahydropyran-2-carboxylic acid ethyl ester using lipase from Alcaligenes sp.

To a 1:1 mixture of (2R,3R,4S,5S) and (2R,3R,4R,5R)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl esters (50 mg, 0.2 mmol) in toluene (3 ml) was added Alcaligenes sp. (40 mg) followed by vinyl acetate (26 μl). The solution was stirred for 5 H at ambient temperature, filtered and the solvent was removed in vacuo. The product was purified by flash chromatography with 20% EtOAc-hexane to give 20 mg of (2R,3R,4S,5S)-3,5-diacetoxy-4-hydroxy-tetrahydropyran-2-carboxylic acid ethyl ester 10 mg of the (2R,3R,4R,5R) diol.

(2R,3R,4S,5S)-3,5-diacetoxy-4-hydroxy-tetrahydropyran-2-carboxylic acid ethyl ester

Colorless oil; R_(f)=0.75 in 100% EtOAc.

¹H NMR (CDCl₃, 400 MHz) δ 5.27 (d, J=8.2 Hz, 1H), 5.10-5.13 (m, 1H), 4.12-4.25 (m, 4H), 3.90-3.95 (m, 2H), 2.14 (s, 3H), 2.10 (s, 3H), 1.27 (t, J=7.2 Hz, 3H).

Example 20 Preparation of (−)-(1R,4S,5S,8R)-8-acetoxyhydroxy-2,6-dioxa-bicyclo[3.2.1]octan-7-one

(2R,3R,4S,5S)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester (300 mg, 1.2 mmol) was dissolved in DMF (5 ml) and the solution was subjected to microwave irradiation at 150° C. for 4H. After cooling, the solvent was removed in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane to give (−)-(1R,4S,5S,8R)-8-acetoxy-4-hydroxy-2,6-dioxa-bicyclo[3.2.1]octan-7-one.

Yield=12%;

IR (neat): 2957, 2923, 2852, 1733, 1463, 1260, 1092, 1019, 799 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 4.77 (br s, 1H), 4.58 (br s, 1H), 4.41 (br s, 1H), 4.03 (dd, J=10.5, 2.8 Hz, 1H), 3.96 (d, J=10.5 Hz, 1H), 3.86 (brs, 1H), 2.18 (s, 3H); ¹³C NMR (CDCl₃, 400 MHz) δ 171.82 (C), 167.19 (C), 79.35 (CH), 77.32 (CH), 72.02 (CH), 70.71 (CH), 64.90 (CH₂), 20.70 (CH₃); EIMS (m/z, relative intensity): 279 (M⁺+77, 17), 160 (37), 159 (57), 148(62), 54(70), 42(99), 31(100);

Example 21 Preparation of (+)-(2R,3R,4S,5S)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid

A solution of (2R,3R,4S,5S-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester (370 mg, 1.49 mmol) in 19 ml of water-ethanol (4:1) was cooled to 0° C. and 1M KOH (2.1 ml) was added dropwise over 30 min. The resulting solution was stirred at 0° C. for 30 min and neutralized by addition of DOWEX-50W-X8 ion exchange resin. The resin was removed by filtration and the filtrate was concentrated in vacuo. The crude product was triturated with isopropanol (2 ml) to afford acid (+)-(2R,3R,4S,5S)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid.

Yield=65%;

IR (neat): 3600-3100, 2924, 1731, 1243, 1101, 1064, 778, 628 cm⁻¹;

¹H NMR (CD₃OD, 400 MHz) δ 3.84-3.88 (m, 1H), 3.75-3.86 (m, 4H), 3.61 (d, J=8.4 Hz, 1H), 3.49-3.51 (m, 1H), 3.45-3.48 (m, 2H); ¹³C NMR (CD₃OD, 100 MHz) δ 173.12 (C), 80.10 (CH), 74.54 (CH), 70.40 (CH), 70.39 (CH₂), 69.52 (CH); EIMS (m/z, relative intensity): 177 (M⁺−1, 5), 160 (12), 149 (22), 73 (43), 57 (65), 43 (100).

Example 22 Preparation of (+)-(1R,4S,5S,8R)-4,8-hydroxy-2,6-dioxa-bicyclo[3.2.1]octan-7-one

To (2R,3R,4S,5S)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid (25 mg, 0.14 mmol) was added diisopropylethylamine (30 μL, 0.169 mmol) followed by dry THF (3 ml) and the resulting solution was cooled to 0° C. Methyl chloroformate (12 μL, 0.154 mmol) was added dropwise over 5 min and the reaction mixture was stirred at room temperature for 36 H. The solvent was removed in vacuo and the crude product was purified by flash chromatography with 70% EtOAc-hexane to give (+)-(1R,4S,5S,8R)-4,8-hydroxy-2,6-dioxa-bicyclo[3.2.1]octan-7-one

Yield=50%;

IR (neat): 3550-3100, 2924, 1732 cm⁻¹;

¹H NMR (CD₃OD, 200 MHz) δ 3.80-4.05 (m, 2H), 3.62-3.78 (m, 2H), 3.50-3.60 (m, 1H), 3.20-3.30 (m, 1H).

Example 23 Preparation of trans-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol

To a solution of trans-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (56 mg, 0.26 mmol) in THF (5 ml) was added LiAlH₄ (62 mg, 1.64 mmol). The resulting solution was stirred at ambient temperature for 15 min and quenched by addition of H₂O (10 ml). The solution was diluted with EtOAc (50 ml×2), washed with brine (50 ml), dried over Na₂SO₄, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane (R_(f)=0.25 in EtOAc) to give 2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol as a colorless liquid

Yield: 30 mg, 89%.

IR (neat): 3100-3600, 2983, 1642, 1376, 1186, 1114, 1038 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 5.77-5.84 (m, 2H), 4.16-4.19 (m, 3H), 3.88 (dd, J=11.5, 3.9 Hz, 1H), 3.78 (dd, J=11.5, 5.5 Hz, 1H), 3.30-3.33 (m, 1H), 1.77 (br s, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ 128.41 (CH), 127.80 (CH), 78.46 (CH), 65.31 (CH₂), 64.42 (CH), 63.24 (CH₂); MS (m/z, relative intensity): 130 (M⁺, 8), 112 (29), 97 (61), 81 (100); exact mass calculated for C₆H₁₀O₃ (M⁺): 130.0630; found 130.0633.

Example 24 Preparation of trans-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol

To a stirred solution of trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (0.480 g, 2.79 mmol) in THF (20 ml) at RT, was added in portions LiAlH₄ (0.126 g, 3.384 mmol) and the resulting mixture was stirred for 30 min. EtOAc (10 ml) was added, the mixture was stirred for 10 min and extracted with water (10 ml×2). The organic layer was dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the crude product purified by flash chromatography (25-30% EtOAc in hexane).

Yield: 0.37 g, 94%;

Example 25 Preparation of cis-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol

To a solution of cis-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (52 mg, 0.25 mmol) in THF (5 ml) was added LiAlH₄ (60 mg, 1.60 mmol). The resulting solution was stirred at ambient temperature for 15 min. The reaction was quenched by addition of H₂O (10 ml). The solution was diluted with EtOAc (50 ml×2), washed with brine (50 ml), dried over Na₂SO₄, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane to give cis-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol

Colorless liquid; Yield: 28 mg, 90%; R_(f)=0.20 in EtOAc

IR (neat): 3050-3600, 2932, 1644, 1447, 1378, 1297, 1185, 1103, 1040 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 5.95-6.05 (m, 2H), 4.12-4.30 (m, 2H), 3.88-3.94 (m, 2H), 3.75-3.85 (m, 1H), 3.55-3.60 (m, 1H), 1.86 (brs, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ 130.60 (CH), 126.41 (CH), 77.87 (CH), 66.18 (CH₂), 63.50 (CH), 63.11 (CH₂); MS (m/z, relative intensity): 129 (M⁺−1, 22), 112 (5), 111 (17), 70 (100); exact mass calculated for C₆H₁₀O₃ (M⁺): 130.0630; found 130.0634.

Example 26 Preparation of cis-2-hydroxymethyl-3,6-hydro-2H-pyran-3-ol

To a stirred solution of cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (0.60 g, 3.48 mmol) in THF (20 ml) at RT, was added in portions LiAlH₄ (0.204 g, 4.89 mmol) and the resulting mixture was stirred for 30 min. EtOAc (10 ml) was added, the mixture was stirred for 10 min and extracted with water (10 ml×2). The organic layer was dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the crude product purified by flash chromatography (25-30% EtOAc in hexane).

Colorless oil; Yield: 0.42 g, 85%. R_(f)=0.18 (EtOAc).

Example 27 Preparation of trans-2-(tert-butyldimethylsilanyloxymethyl)-3,6-dihydro-2H-pyran-3-ol

To a 0° C., stirred solution of trans-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol (OA g, 2.84 mmol) in CH₂Cl₂ (40 ml) under an Argon atmosphere was added imidazole (0.231 g, 3.4 mmol) followed by TBSCl (0.428 g, 3.4 mmol). The resulting mixture was stirred for 1H at 0° C. The reaction mixture was washed with water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na₂SO₄ The solvent was removed in vacuo and the crude product purified by flash chromatography (25-40% EtOAc in hexane).

Colorless oil. Yield: 0.618 g, 84%. R_(f)=0.72 (1:1 ether-hexane).

IR (neat): 3600-3100, 3037, 2929, 2857, 1463, 1254, 1099, 837, 778 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz)

5.76-5.77 (m, 2H), 4.15-4.20 (m, 1H), 4.06-4.10 (m, 2H), 3.89 (dd, J=10.0, 5.2 Hz, 1H), 3.71 (dd, J=7.4, 10.0 Hz, 1H), 3.30-3.36 m, 1H), 0.88 (s, 9H), 0.08 (s, 6H);

¹³C NMR (CDCl₃, 100 MHz) δ 127.97 (CH), 127.05 (CH), 77.32 (CH), 67.02 (CH), 65.73 (CH₂), 65.21 (CH₂), 25.83 (3×CH₃), 18.21 (C), −5.53 (CH₃), −5.59 (CH₃),

MS (m/z, relative intensity): 189 (4, M⁺-tert-But), 118 (78), 116 (100)

Example 28 Preparation of cis-2-(tert-butyldimethylsilanyloxymethyl)-3,6-dihydro-2H-pyran-3-ol

To a 0° C., stirred solution of cis-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol (0.4 g, 2.84 mmol) in CH₂Cl₂ (40 ml) under an Argon atmosphere was added imidazole (0.231 g, 3.4 mmol) followed by TBSCl (0.428 g, 3.4 mmol). The resulting mixture was stirred for 1H at 0° C. The reaction mixture was washed with water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the crude product purified by flash chromatography (25-40% EtOAc in hexane).

Colorless oil. Yield: 0.478 g, 65%. R_(f)=0.6 (1:1, ether-hexane).

IR (neat): 3500-3150, 2928, 2925, 1103 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 5.99-6.03 (m, 1H), 5.89-5.93 (m, 1H), 4.19 (dd, J=3.4, 1.7 Hz, 1H), 4.11 (dd, J=16.9, 2.0 Hz, 1H), 3.93-3.95 (m, 1H), 3.50-3.85 (m, 2H), 3.49-3.52 (m, 1H), 1.90-2.00 (m, 1H), 0.88 (s, 9H), 0.07 (s, 6H)

¹³C NMR (CDCl₃, 100 MHz) δ 130.26 (CH), 126.62 (CH), 78.12 (CH), 66.14 (CH₂), 62.85 (CH₂), 62.57 (CH), 25.87 (3×CH₃), 18.28 (C), −5.36 (CH₃), -5.41 (CH₃)

MS (m/z, relative intensity): 203 (M+−41), 185 (25), 173 (48), 143 (41), 131 (71), 117 (100).

MS (EI) calcd. for C₁₂H₂₄O₃Si 244.1495.

Example 29 Preparation of 4-(tert-buyldimethylsilanyloxymethyl)-3,7-dioxa-bicyclo[4.1.0]heptan-5-ol

To a 0° C., stirred solution of trans-2-(tert-butyldimethylsilanyloxymethyl)-3,6-dihydro-2H-pyran-3-ol (0.110 g, 0.45 mmol) in CH₂Cl₂ (10 ml) was added m-CPBA (75%, 0.108 g, 1.08 mmol) and the mixture was stirred for 1 h at 0° C. Dimethyl sulfide (0.01 ml) was added and stirring was continued for 10 min. The solvent was removed in vacuo and the crude product was diluted with EtOAc (30 ml). The resulting solution was washed successively with saturated aqueous Na₂CO₃ (10 ml), water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the crude product was purified by flash chromatography (2540% EtOAc in hexane).

Colorless oil. Yield: 0.094 g, 80%. R_(f)=0.47 (1:1 ether-hexane).

IR (neat): 3550-3100, 2954, 2928, 2856, 1463, 1254, 1146, 1102, 837, 778 cm⁻¹;

¹H NMR (acetone-d₆, 400 MHz) δ 4.11 (d, J=7.2 Hz, 1H), 4.03 (dd, J=13.4, 3.9 Hz, 1H), 3.87 (dd, J=10.5, 2.2 Hz, 1H), 3.84-3.81 (m, 1H), 3.73-3.64 (m, 2H), 3.45 (dd, J=4.2, 4.2 Hz, 1H), 3.35-3.38 (m, 1H), 3.20-3.15 (m, 1H), 0.89 (s, 9H), 0.05 (s, 6H);

¹³C NMR (acetone-d₆, 100 MHz)

76.75 (CH), 66.45 (CH), 65.19 (CH₂), 64.31 (CH₂), 55.73 (CH), 54.95 (CH), 26.25 (3×CH₃), 18.90 (C), −5.11 (CH₃), −5.14 (CH₃); MS (m/z, relative intensity): 203 (M⁺-t-Bu, 17), 173 (3), 117 (53), 75 (100).

Example 30 Preparation of (1S,4S,5R,6R) and (1R,4S,5R,6S)-4-(tert-butyl-dimethylsilanyloxymethyl)-3,7-dioxa-bicyclo[4.1.0]heptan-5-ol

To a 0° C., stirred solution of cis-2-(tert-butyldimethylsilanyloxymethyl)-3,6-dihydro-2H-pyran-3-ol (0.200 g, 0.91 mmol) in CH₂Cl₂ (15 ml) was added m-CPBA (75%, 0.46 g, 2.68 mmol) and the mixture was stirred for 1 H at 0° C. Dimethyl sulfide (0.01 ml) was added and stirring was continued for 10 min. The solvent was removed in vacuo and the crude product was diluted with EtOAc (30 ml). The resulting solution was washed successively with saturated aqueous Na₂CO₃ (10 ml), water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the crude product was purified by flash chromatography (25-40% EtOAc in hexane).

(1S,4S,5R,6R)-4-(tert-butyl-dimethylsilanyloxymethyl)-3,7-dioxa-bicyclo[4.1.0]heptan-5-ol

Yield: 0.083 g, 39%. R_(f)=0.52 (30% EtOAc-hexane).

IR (neat): 3550-3150, 2928, 2855, 1256, 1099, 839, 777 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 4.16 (d, J=13.4 Hz, 1H), 3.89-3.95 (m, 1H), 3.70-3.78 (m, 2H), 3.62 (dd, J=10.5, 6.3 Hz, 1H), 3.55 (dd, J=5.6, 4.0 Hz, 1H), 3.23 (d, J=3.9 Hz, 1H), 3.14 (ddd, J=8.7, 6.4, 2.4 Hz, 1H), 2.37 (d, J=11.0 Hz, 1H), 1.23 (brs, 1H), 0.88 (s, 9H), 0.05 (s, 6H);

¹³C NMR (CDCl₃, 100 MHz) δ 78.86 (CH), 64.70 (CH₂), 61.66 (CH₂), 61.31 (CH), 52.26 (CH), 51.63 (CH), 25.86 (3×CH₃), 18.28 (C), −5.37 (CH₃), −5.44 (CH₃);

MS (m/z, relative intensity): 203 (M+-t-Bu, 4), 185 (22), 173 (45), 131 (70), 117 (100).

(1R,4S,5R,6S)-4(tert-butyl-dimethylsilanyloxymethyl)-3,7-dioxa-bicyclo[4.1.0]heptan-5-ol

Yield: 0.10 g, 41%. R_(f)=0.32 (30% EtOAc-hexane).

IR (neat): 3550-3100, 2928, 2856, 1254, 1103, 837, 777 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 4.18 (dd, J=13.6, 3.9 Hz, 1H), 1.43 (d, J=6.4 Hz, 1H), 3.93 (d, J=13.5 Hz, 1H), 3.75 (dd, J=5.7, 2.4 Hz, 2H), 3.42-3.39 (m, 1H), 3.38-3.36 (m, 1H), 3.28 (dd, J=4.0, 4.0 Hz, 1H), 2.87 (d, J=7.0 Hz, 1H), 1.62 br s, 1H), 0.86 (s, 9H), 0.07 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz) δ 72.51 (CH), 65.32 (CH), 65.07 (CH₂), 63.33 (CH₂), 52.74 (CH), 51.26 (CH), 25.86 (3×CH₃), 18.22 (C), —5.50 (2×CH₃);

Example 31 Preparation of 5-benzyloxy-2-hydroxymethyl-tetrahydropyran-3,4-diol

A solution of 4-(tert-butyldimethylsilanyloxymethyl)-3,7-dioxabicyclo[4.1.0]heptan-5-ol (0.06 g, 0.228 mmol) in CH₂Cl₂ (10 ml) was stirred under Argon atmosphere at RT for 15 min. Yttrium triflate (0.048 g, 0.08 mmol) was added and the slurry was stirred for 10 min. Benzyl alcohol (120 μl, 0.912 mmol) was added and the mixture was stirred for 24 H. The solvent was removed and the crude product was diluted with EtOAc (20 ml), washed with water (10 ml), saturated aqueous NaHCO₃ (5 ml×2) and brine (5 ml). The organic phase was dried over anhydrous Na₂SO₄. The crude product was purified by flash chromatography using 60% MeOH in EtOAc

Yield: 0.030 g, 51%. R_(f)=0.18 (EtOAc).

IR (neat): 3600-3100, 3030, 2928, 2856, 1454, 1254, 1103, 837, 698 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 7.28-7.33 (m, 5H), 4.48-4.62 (d, 1H, J=12 Hz), 4.57 (d, 1H, J=12 Hz, 2.3 Hz), 4.07-4.12 (m, 2H), 3.93-4.0 (m, 1H), 3.83-3.9 (m, 1H), 3.8-3.85 (m, 1H), 3.75-3.78 (m, 1H), 3.54-3.5.8 (m, 1H), 3.53-3.54 (m, 1H);

¹³C NMR (CDCl₃, 100 MHz) δ 138.29 (C), 128.90 (2×CH), 128.27 (CH), 128.09 (2×CH), 76.50 (CH), 75.01 (CH), 71.66 (CH₂), 68.77 (CH), 67.25 (CH), 64.69 (CH₂), 63.99 (CH₂); MS (m/z, relative intensity): 255 (M⁺+1, 17), 254 (M⁺, 16), 206 (6), 176 (10), 107 (20), 91 (100); HRMS calcd. for C₁₃H₁₈O₅: 254.1155; observed: 254.1164.

Example 32 Preparation of 5-benzylamino-2-(tert-butyldimethylsilanyloxymethyl)-tetrahydropyran-3,4-diol

Following the procedure of example 32, the crude product was purified by flash chromatography using 10-20% EtOAc in hexane.

Yield: 0.045 g (53% yield). R_(f)=0.18 (1:1 EtOAc-hexane).

IR (neat): 3580, 3500-3200, 2927, 2857, 1464, 1252, 1086, 1062, 838, 780 cm⁻¹;

¹H NMR (CDCl₃, 200 MHz) δ 7.20-7.30 (m, 5H), 4.00-4.03 (m, 1H), 3.72-3.90 (m, 5H), 3.60-3.70 (m, 2H), 3.48-3.58 (m, 1H), 2.81 (dd, J=3.5, 1.7 Hz, 1H), 0.89 (s, 9H), 0.08 (s, 6H). ¹³C NMR (CDCl₃, 100 MHz) δ 139.88 (C), 128.44 (2×CH), 128.09 (2×CH), 127.10 (CH), 73.78 (CH), 69.53(CH), 69.11 (CH), 65.78 (CH₂), 64.78 (CH₂), 56.80 (CH), 51.66 (CH₂), 25.80 (3×CH₃), 18.16 (C), −5.57 (CH₃), −5.62 (CH₃); MS (m/z, relative intensity): 367 (M⁺, 11), 310 (M-t-Bu, 22), 148 (22), 91 (PhCH₂ ⁺, 100); MS (EI) calcd. for C₁₉H₃₃NO₄Si: 367.2179; observed: 367.2171.

X-ray crystal structure of 5-benzylamino-2-(tert-butyldimethylsilanyloxymethyl)-tetrahydropyran-3,4-diol

Example 33 Preparation of 2-hydroxymethyl-tetrahydropyran-3,4,5-triol

A solution of 4-(tert-butyldimethylsilanyloxymethyl)-3,7-dioxabicyclo[4.1.0]heptan-5-ol (0.06 g, 0.23 mmol) in CH₂Cl₂ (10 ml) was stirred under Argon atmosphere at RT for 15 min. BF₃.OEt₂ (1.5 ml, 0.013 mmol) was added followed by water (12 ml, 0.65 mmol). After stirring the mixture for 24 h, the solvent was removed and the crude product was purified by flash chromatography using 10% MeOH in EtOAc.

Yield: 0.015 g, 44%. R_(f)=0.1 (EtOAc).

¹H NMR (D₂O, 400 MHz) δ 4.04 (dd, J=13.8, 1.5 Hz, 1H), 3.84 (dd, J=11.6, 2.1 Hz, 1H), 3.78-3.70 (m, 2H), 3.60 (dd, J=4.2, 4.2 Hz, 1H), 3.50-3.42 (m, 2H), 3.22-3.15 (m, 1H);

¹³C NMR (D₂O, 100 MHz) δ 75.36, 65.13, 64.44, 61.43, 56.58, 54.99.

Example 34 Preparation of 6-(tert-butyldimethylsilanyloxymethyl)-5-hydroxy-4-trimethylsilanyloxy-tetrahydro-pyran-3-carbonitrile

A solution of 4-(tert-butyldimethylsilanyloxymethyl)-3,7-dioxabicyclo[4.1.0]heptan-5-ol (0.02 g, 0.077 mmol) in CH₂Cl₂ (5 ml) was stirred under Argon atmosphere at RT for 15 min. Yttrium triflate (0.024 g, 0.04 mmol) was added and the slurry was stirred for 10 min. TMSCN (0.022 g, 25 ml, 0.228 mmol) was added and the mixture was stirred for 24 H. The solvent was removed and the crude product was diluted with EtOAc (20 ml), washed with water (10 ml), saturated aqueous NaHCO₃ (5 ml×2) and brine (5 ml). The organic phase was dried over anhydrous Na₂SO₄. The crude product was purified by flash chromatography using 10% EtOAc in hexane.

Yield: 0.018 g, 64%. R_(f)=0.73 (1:1 EtOAc-hexane).

IR (neat): 3550-3100, 2925, 2359, 774 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 4.00-4.10 (m, 2H), 3.72-3.82 (m, 2H), 3.60-3.70 (m, 1H), 3.42 (dd, J=4.1, 4.1 Hz, 1H), 3.28-3.30 (m, 1H), 3.15-3.20 (m, 1H), 0.87 (s, 9H), 0.17 (s, 9H), 0.03 (s, 6H);

¹³C NMR (CDCl₃, 100 MHz) δ 76.02 (CH), 66.50 (CH), 64.95 (CH₂), 63.03 (CH₂), 56.04 (CH), 55.03 (CH), 26.40 (3×CH₃), 18.90 (C), 0.74 (3×CH₃), -4.77 (2×CH₃), 4.89 (2×CH₃);

MS (m/z, relative intensity): 333 (M⁺-CN, 78), 307 (100), 289 (70).

Example 35 Preparation of 5-azido-2-(tert-butyldimethylsilanyloxymethyl)-tetrahydropyran-3,4-diol

A solution of 4-(tert-butyldimethylsilanyloxymethyl)-3,7-dioxabicyclo[4.1.0]heptan-5-ol (0.03 g, 0.12 mmol) in MeOH (4 ml) was treated with water (1 ml) and NaN₃ (0.042 g, 0.65 mmol). The resulting mixture was heated to reflux for 12 H. The solvent was removed in vacuo. The crude product was diluted with EtOAc (10 ml), washed with water (5 ml×2), saturated aqueous Na₂CO₃ solution (5 ml) and brine (5 ml). The organic phase was dried over anhydrous Na₂SO₄. The crude product was purified by flash chromatography using 20-25% EtOAc in hexane.

Yield: 0.021 g, 58%. R_(f)=0.47 (1:1 EtOAc-hexane).

IR (neat): 3500-3100, 2928, 2108, 1256, 1101, 837, 776 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 4.40 (d, J=3.4 Hz, 1H), 3.85-3.95 (m, 3H), 3.64-3.82 (m, 3H), 3.49-3.55 (m, 1H), 2.89 (brs, 2H), 0.89 (s, 9H), 0.07 (s, 6H);

¹³C NMR (CDCl₃, 100 MHz) δ 77.88, 69.58, 65.91, 64.46, 64.13, 61.94, 26.26 (three CH₃), 18.89, −5.11, −5.12;

MS (m/z, relative intensity): 304 (20, M⁺+1), 246 (38), 75 (100).

Example 36 Preparation of 2-(tert-butyldimethylsilanyloxymethyl)-5-(3-methoxyphenylamino)-tetrahydropyran-3,4-diol

A solution of 4-(tert-butyldimethylsilanyloxymethyl)-3,7-dioxabicyclo[4.1.0]heptan-5-ol (0.03 g, 0.13 mmol) and m-anisidine (0.08 g, 0.65 mmol) in DMF (4 ml) was heated to reflux for 12H. The solvent was removed in vacuo and the crude product was purified by flash chromatography using 15-25% EtOAc in hexane.

Yield: 0.027 g, 53%. R_(f)0.48 (1:1 EtOAc-hexane).

IR (neat): 3550-3100, 2953, 2928, 2856, 1615, 1254, 1092, 836, 778 cm⁻¹;

¹H NMR (CDCl₃, 200 MHz) δ 7.00-7.19 (m, 1H), 6.16-6.39 (m, 2H), 3.50-4.20 (m, 8H), 3.75 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H);

Example 37 Preparation of 2-(tert-butyl-dimethylsilanyloxymethyl)-5-phenylsulfanyl-tetrahydropyran-3,4-diol

A solution of 4-(tert-butyldimethylsilanyloxymethyl)-3,7-dioxabicyclo[4.1.0]heptan-5-ol (30 mg, 0.115 mmol) in benzene (5 mL) was stirred under Argon atmosphere. Titanium tetraisopropoxide (85 mg, 0.3 mmol) and thiophenol (12 μL, 13 mg, 0.115 mmol) were added sequentially and the resulting mixture was stirred for 24 H. The solvent was removed in vacuo and the residue was diluted with EtOAc (20 mL), washed with water (5 mL×2), saturated aqueous sodium carbonate solution (5 mL) and brine (5 mL). The organic phase was dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the crude product was purified by flash chromatography using 10-20% EtOAc-hexane.

Yield: 0.019 g, 45%. R_(f)=0.82 (1:1 EtOAc-hexane).

IR (neat): 3500-3100, 2925, 1090, 775 cm⁻¹;

¹H NMR (CDCl₃, 200 MHz) δ 7.38-7.42 (m, 2H), 7.24-7.31 (m, 3H), 4.20-3.20 (m, 6H), 2.89-2.86 (m, 2H), 0.89 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H);

MS (EI) calcd. for C₁₈H₃₀O₄SSi 370.1634; observed. 313 (6, M⁺-t-Bu), 312 (7), 204 (20), 123 (48), 118 (78), 117 (100).

Example 38 Preparation of (2S,3S,4S,5R)-5-benzylamino-2-(tert-butyldimethylsilanyloxymethyl)-tetrahydropyran-3,4-diol

Following the procedure of example 32, the crude product was purified by flash chromatography using 60% EtOAc in hexane.

Yield: 72%. R_(f)=0.3 (1:1 EtOAc-hexane).

IR (neat): 3550-3200, 2927, 2855, 1254, 1104, 837, 776, 699 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 7.23-7.34 (m, 5H), 3.80-4.05 (m, 7H), 3.86 (br s, 2H), 3.67 (brs, 1H), 3.50 (brs, 1H), 3.12 (brs, 1H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H).

¹³C NMR (CDCl₃, 100 MHz) δ 139.88 (C), 128.49 (2×CH), 128.02 (2×CH), 127.24 (CH), 72.95 (CH), 71.34 (CH), 69.35 (CH₂), 68.23 (CH), 66.29 (CH₂), 58.72 (CH), 52.32 (CH₂), 25.77 (3×CH₃), 18.18 (C), −5.52 (CH₃), −5.66 (CH₃);

MS (m/z, relative intensity): 367 (M⁺, 2), 311 (10), 179 (15), 149 (15), 106 (15), 91 (100);

MS (EI) calcd. for C₁₉H₃₃NO₄Si: 367.2179; observed: 367.2184.

Example 39 Preparation of (2S,3S,4R,5S)-5)-benzylamino-2-(tert-butyldimethylsilanyloxymethyl)-tetrahydropyran-3,4-diol

Following the procedure of example 32, the crude product was purified by column chromatography using 60% EtOAc in hexane.

Yield: 63%. R_(f)=0.33 (1:1 EtOAc-hexane).

IR (neat): 3550-3200, 2927, 2856, 1462, 1254, 1074, 838, 778, 750, 699 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 7.24-7.34 (m, 5H), 4.12-4.13 (m, 1H), 4.01 (d, J=1.4 Hz, 1H), 3.90-3.70 (m, 6H), 3.64 (br s, 1H), 2.77 (br s, 1H), 1.24 (br s, ₁H), 0.88 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 138.31 (C), 128.71 (2×CH), 128.25 (2×CH), 127.60 (CH), 76.01 (CH), 69.90 (CH), 66.37 (CH), 66.11 (CH₂), 63.24 (CH₂), 57.00 (CH), 51.54 (CH₂), 25.94 (C), 18.37 (3×CH₃), −5.33 (CH₃), −5.37 (CH₃); MS (m/z, relative intensity): 367 (M⁺, 11), 311 (31), 149 (30), 107 (39), 92 (100); MS (EI) calcd. for C₁₉H₃₃NO₄SI: 367.2179; observed: 367.2175.

Example 40 Preparation of 2-allyloxy-3-hydroxy-hex-4-enoic acid ethyl ester

A solution of lithium diisopropylamide (LDA) in THF/n-heptane (4.27 mL, 2M, 8.28 mmol) was added to THF (40 mL) at −78° C. and the mixture was stirred for 5 min under argon atmosphere. A solution of allyloxyacetic acid ethyl ester (1 g, 6.9 mmol) in THF (10 mL) was added and stirring was maintained for 5 min. Distilled crotonaldehyde (0.68 mL, 8.28 mmol) was added into the reaction mixture and the resulting solution was allowed to stir for 25 min. The reaction was quenched by the addition of EtOH (5 mL) and the solution was allowed to warm to RT. The solution was diluted with EtOAc (50 mL) and washed with water (10 mL). The organic layer was dried over Na₂SO₄, concentrated in vacuo and the residue was purified by flash chromatography with 15% EtOAc-hexane.

Yield=0.76 g (51%); R_(f)=0.33, 40% EtOAc-hexane

¹H NMR (200 MHz, CDCl₃) δ 1.25 (t, J=7.0 Hz, 3H), 1.68 (d, J=5.8 Hz, 3H), 3.85-4.05 (m, 1H), 4.08-4.30 (m, 4H), 5.12-5.38 (m, 2H), 5.40-5.60 (m, 1H), 5.62-6.00 (m, 2H); ¹³C NMR (125 MHz, ca. 2:1, for major isomer): δ 170.21 (C), 133.71 (CH), 129.46 (CH), 128.24 (CH), 118.26 (CH₂), 81.06 (CH), 74.92 (CH), 73.44 (CH₂), 60.94 (CH₂), 17.72 (CH₃), 14.19 (CH₃); MS (m/z, relative intensity): 214 (M⁺, 3), 196 (36), 155 (58), 127 (21), 71 (100).

HRMS calculated for C₁₁H₁₈O₄: 214.1205, found 214.1204.

Example 41 Preparation of cis- and trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

To a stirred solution of 2-allyloxy-3-hydroxy-hex-4-enoic acid ethyl ester (0.1 g, 0.47 mmol) in dry benzene (20 mL) was added bis-(tricyclohexylphosphine)-benzylidine rutherium (IV) chloride (15 mg, 0.018 mmol) and the mixture was stirred at ambient temperature. The solvent was removed and the residue was purified by flash chromatography with 20-40% EtOAc-hexane.

trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=56%;

cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=25%

Example 42 Preparation of 2-allyloxy-3-hydroxy-5-phenyl-pent 4-enoic acid ethyl ester

A 2.0M solution of LDA in THF/n-heptane (4.27 mL, 8.28 mmol) was added to THF (40 mL) at −78° C. and stirred for 5 min under argon atmosphere. A solution of allyloxyacetic acid ethyl ester (1 g, 6.9 mmol) in THF (20 mL) was added and the reaction mixture was stirred for 25 min. Distilled cinnamaldehyde (1 mL, 8.28 mmol) was added into the reaction mixture and the resulting solution was allowed to stir for 15 min. The reaction was quenched by the addition of EtOH (5 mL) and the solution was allowed to warm to RT. EtOAc (150 mL) was added and the organic layer was washed with water (10 mL), dried over Na₂SO₄, concentrated in vacuo and the residue was purified by flash chromatography with 18% EtOAc-hexane.

Yield=1.37 g (68%); R_(f)=0.25, 20% EtOAc-hexane

¹H NMR (500 MHz, CDCl₃, two isomers): δ 7.20-7.40 (m, 5H), 6.66 (dd, J=15.5, 6.0 Hz, 1H), 6.30-6.20 (m, 1H), 5.95-5.85 (m, 1H), 5.22 (dd, J=10.5, 1.0 Hz, 2H), 4.65-4.50 (m, 1H), 4.35-4.18 (m, 2H), 4.15-3.95 (m, 2H), 1.23 (t, J=7.0 Hz, 3H);

¹³C NMR (125 MHz, CDCl₃, two isomers, ca. 1:1 ratio): δ 170.44 (C), 170.15 (C), 136.34 (C), 136.25 (C), 133.57 (CH), 133.46 (CH), 132.53 (CH), 132.31 (CH), 128.46 (2×CH) 128.41 (2×CH) 128.33 (CH), 127.81 (CH), 127.72 (CH), 126.72 (CH), 126.54 (2×CH), 126.51 (2×CH), 118.48 (CH₂), 118.36 (CH₂), 81.20 (CH), 80.95 (CH), 73.36 (CH), 72.95 (CH), 71.99 (2×CH₂), 61.12 (CH₂), 61.02 (CH₂), 14.16 (CH₃), 14.11 (CH₃).

MS (m/z, relative intensity): 276 (M⁺, 2), 263 (10), 144 (51), 133 (63), 115 (50), 103 (100);

HRMS calculated for C₁₆H₂₀O₄: 276.1362; found 276.1360.

Example 43 Preparation of cis- and trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

To a stirred solution of 2-allyloxy-3-hydroxy-5-phenyl-pent-4-enoic acid ethyl ester (90 mg, 0.33 mmol) in dry DCM (20 mL) was added bis-(tricyclohexylphosphine)-benzylidine rutherium (IV) chloride (16 mg, 0.018 mmol) and the mixture was stirred at ambient temperature for 30 h. The solvent was removed and the residue was purified by flash chromatography with 20-40% EtOAc-hexane.

trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=49%;

cis-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=26%;

Example 44 Preparation of 3-acetoxy-2-allyloxy-pent-4-enoic acid ethyl ester

To a solution of 2-allyloxy-3-hydroxy-pent-4-enoic acid ethyl ester (100 mg, 0.5 mmol) and DMAP (30 mg, 0.25 mmol) in CH₂Cl₂-Et₃N (9:1, 10 mL) was added Ac₂O (76 mg, 0.75 mmol). The resulting solution was stirred at ambient temperature for 1H. The solution was diluted with CH₂Cl₂ (40 mL), washed with H₂O (20 mL×2), dried over Na₂SO₄, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane.

Yield=119 mg, 99% yield; colorless liquid; R_(f)=0.58 in 20% EtOAc-hexane.

IR (neat): 2967, 1747, 1369, 1236, 1028, 932 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz): δ 5.80-6.00 (m, 2H), 5.50-5.68 (m, 1H), 5.15-5.40 (m, 4H), 3.90-4.30 (m, 5H), 2.02 (br s, 3H), 1.25 (t, J=7 Hz, 3H);

¹³C NMR (CDCl₃, 100 MHz, 2:1 isomeric forms, * denotes minor isomer): δ 169.64* (C), 169.53 (C), 169.34* (C), 169.29 (C), 133.55* (CH), 133.49 (CH), 132.02* (CH), 131.59 (CH), 119.31 (CH₂), 119.16* (CH₂), 118.27* (CH₂), 118.10 (CH₂), 79.00 (CH), 78.89* (CH), 74.44 (CH), 74.17* (CH), 72.08* (CH₂), 71.89 (CH₂), 61.11 (*CH₂ and CH₂), 20.90 (CH₃), 20.80* (CH₃), 14.12 (CH₃), 14.06* (CH₃);

MS (m/z, relative intensity): 242 (M⁺, 19), 200 (22), 169 (41), 142 (13), 110 (100); HRMS calculated for C₁₂H₁₈O₅ (M⁺): 242.1154; found 242.1160.

Example 45 Preparation of cis- and trans-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

To a solution of 3-acetoxy-2-allyloxy-pentenoic acid ethyl ester (300 mg, 1.23 mmol) in CH₂Cl₂ (10 mL) was added bis-(tricyclohexylphosphine)-benzylidine rutherium (IV) chloride (20 mg, 0.024 mmol), the resulting mixture was stirred at ambient temperature for 4 H and bis-(tricyclohexylphosphine)-benzylidine rutherium (IV) chloride (20 mg, 0.024 mmol) was added again. The resulting mixture was stirred at ambient temperature for an additional 10 h. The solution was concentrated in vacuo and purified by flash chromatography with 15 to 20% EtOAc-hexane.

trans-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=127 mg, 48%; R_(f)=0.43 in 20% EtOAc-hexane; IR (neat): 2967, 1747, 1374, 1231, 1028 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 5.96 (dd, J=10.4, 1.0 Hz, 1H), 5.80-5.85 (m, 1H), 5.44 (br s, 1H), 4.40 (dd, J=2.4, 17.3 Hz, 1H), 4.10-4.25 (m, 4H), 2.03 (s, 3H), 1.23 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 170.25 (C), 168.87 (C), 130.63 (CH), 122.00 (CH), 74.49 (CH), 65.33 (CH), 63.63 (CH₂), 61.50 (CH₂), 20.96 (CH₃), 14.02 (CH₃); MS (m/z, relative intensity): 215 (M⁺+1, 6), 213 (M⁺−1, 18), 153 (100), 149 (30); HRMS calculated for C₁₀H₁₄O₅ (M⁺): 214.0841; found 214.0844.

cis-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Yield=117 mg, 43%; R_(f)=0.16 in 20% EtOAc-hexane; IR (neat): 2980, 2932, 2831, 1738, 1375, 1234, 1105, 1023 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 5.95-6.10 (m, 2H), 5.30-5.35 (m, 1H), 4.41 (dd, J=3.4, 1.6 Hz, 1H), 4.15-4.40 (m, 4H), 2.00 (s, 3H), 1.25 (t, J=7.2 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 170.12 (C), 167.91 (C), 132.06 (CH), 121.72 (CH), 75.12 (CH), 65.77 (CH₂), 64.87 (CH), 61.33 (CH₂), 20.67 (CH₃), 14.14 (CH₃); MS (m/z, relative intensity): 215 (M⁺+1, 6), 213 (M⁺−1, 18), 153 (100), 149 (30); exact mass calculated for C₁₀H₁₄O₅ (M⁺): 214.0841; found 214.0839.

Example 46 Preparation of trans-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

To a solution of trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (70 mg, 0.41 mmol) and DMAP (24 mg, 0.2 mmol) in CH₂Cl₂-Et₃N (9:1, 5 mL) was added Ac₂O (54 mg, 0.53 mmol). The resulting solution was stirred at ambient temperature for 2 H. The solution was diluted with CH₂C₁₂ (40 mL), washed with H₂O (20 mL×2), dried over Na₂SO₄, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane.

Yield=68 mg, 79%; colorless liquid; R_(f)=0.16 in 20% EtOAc-hexane;

Example 47 Preparation of 2-allyloxy-pent-4-ene-1,3-diol

To a solution of 2-allyloxy-3-hydroxy-pentenoic acid ethyl ester (200 mg, 1.00 mmol) in THF (5 mL) was added LiAlH₄ (151 mg, 4.00 mmol). The resulting solution was stirred at ambient temperature for 15 min. H₂O (10 mL) was added and the mixture was diluted with EtOAc (50 mL×2), washed with brine (50 mL), dried over Na₂SO₄, concentrated in vacuo and purified by flash chromatography with 50% EtOAc-hexane

Yield=112 mg, 71% yield; colorless liquid; R_(f)=0.33 in 60% EtOAc-hexane.

IR (neat): 3100-3700, 2880, 1644, 1425, 1055, 996 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 5.79-5.89 (m, 2H), 5.10-5.31 (m, 4H), 4.04-4.26 (m, 2H), 3.65-3.70 (m, 2H), 3.27-3.30 (m, 1H), 3.01-3.04 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz, * denotes minor isomer): δ 136.98 (CH₂), 134.45 (CH₂), 117.38* (CH), 117.33 (CH), 116.57* (CH), 116.03 (CH), 81.34* (CH₂), 81.11 (CH₂), 72.45 (CH₂), 71.85* (CH), 71.07 (CH), 61.16 (CH); MS (m/z, relative intensity): 127 (M⁺−31, 2), 101 (19), 83 (18), 57 (51); exact mass calculated for C₈H₁₄O₃ (M⁺): 158.0943; found 158.0949.

Example 48 Preparation of cis- and trans-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane

To a solution of 2-allyloxy-pentene-1,3-diol (100 mg, 0.63 mmol) In dry benzene (10 ml) was added 2,2-dimethoxypropane (0.39 ml, 3.15 mmol). The resulting solution was stirred for 5 min at ambient temperature, p-TsOH (12 mg, 0.06 mmol) was added and stirring was maintained for ca. 8 H. Aqueous NaHCO₃ (10 ml) was added and the mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), dried over Na₂SO₄, concentrated in vacuo and purified by flash chromatography with 7% EtOAc-hexane.

trans-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane

Yield=48 mg, 39% yield; colorless liquid; R_(f)=0.83 in 15% EtOAc-hexane;

IR (neat): 2992, 1632, 1455, 1375, 1201, 1094 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 5.71-5.92 (m, 2H), 5.34 (d, J=17.3 Hz, 1H), 5.12-5.23 (m, 3H), 4.06-4.10 (m, 1H), 3.95-3.97 (m, 2H), 3.90 (J=11.4, 5.4 Hz, 1H), 3.62 (dd, J=11.3, 9.1 Hz, 1H), 3.18-3.23 (m, 1H), 1.44 (s, 3H), 1.36 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 136.62 (CH), 135.15 (CH), 118.03 (2×CH₂), 99.25 (C), 74.85 (CH), 74.43 (CH), 72.04 (CH₂), 63.34 (CH₂), 29.20 (CH₃), 20.04 (CH₃); MS (m/z, relative intensity): 198 (M⁺, 2), 183 (15), 142 (19), 84 (90), 83 (38); exact mass calculated for C₁₁H₁₈O₃ (M⁺): 198.1256; found 198.1255.

cis-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane

Yield=44 mg, 36% yield; colorless liquid; R_(f)=0.55 in 15% EtOAc-hexane; IR (neat): 2989, 1647, 1455, 1374, 1196, 1087, 993 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ 5.94-6.03 (m, 1H), 5.81-5.88 (m, 1H), 5.11-5.33 (m, 4H), 4.37 (dd, J=5.4, 1.5 Hz, 1H), 3.90-4.15 (m, 4H), 3.18-3.20 (m, 1H), 1.43 (s, 3H), 1.42 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 135.54 (CH), 134.97 (CH), 117.21 (CH₂), 116.98 (CH₂), 98.72 (C), 73.24 (CH), 72.22 (CH), 70.86 (CH₂), 62.09 (CH₂), 29.02 (CH₃), 19.16 (CH₃); MS (m/z, relative intensity): 183 (M⁺−15, 8), 142 (5), 84 (100), 83 (38); exact mass calculated for C₁₁H₁₈O₃ (M⁺): 198.1256; found 198.1254.

Example 49 Preparation of trans-2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine

To a solution of trans-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane (300 mg, 1.52 mmol) in dry CH₂Cl₂ (10 mL) was added bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) chloride (125 mg, 0.15 mmol). The mixture was stirred at ambient temperature for ca. 8H, filtered through filter paper and concentrated in vacuo to 1 mL. The residue was purified by flash chromatography with 5% EtOAc-hexane

Yield=84% yield; colorless oil; R_(f)=0.48 in 10% EtOAc-hexane; 215 mg,

IR (neat): 3200-3600, 2976, 1747, 1185, 1111, 1024 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 5.70-5.79 (m, 1H), 5.66-5.69 (m, 1H), 4.14-4.28 (m, 3H), 3.88 (dd, J=11.0, 5.0 Hz, 1H), 3.72 (dd, J=10.4, 10.8 Hz, 1H), 3.28-3.34 (m, 1H), 1.49 (s, 3H), 1.39 (s, 3H);

¹³C NMR (CDCl₃, 100 MHz) δ 127.19 (CH), 126.80 (CH), 99.65 (C), 71.37 (CH), 67.61 (CH), 66.39 (CH₂), 63.15 (CH₂), 29.24 (CH₃), 19.06 (CH₃);

MS (m/z, relative intensity): 170 (M⁺, 5), 169 (55), 97 (91), 83 (54), 70 (100); HRMS calculated for C₉H₁₄O₃ (M⁺): 170.0943; found 170.0944.

Example 50 Preparation of cis-2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine

To a solution of cis-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane (300 mg, 1.52 mmol) in dry CH₂Cl₂ (10 mL) was added bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) chloride (120 mg, 0.14 mmol). The mixture was stirred at ambient temperature for ca. 8 H, filtered through filter paper and concentrated in vacuo to 1 mL. The residue was purified by flash chromatography with 15% EtOAc-hexane

Yield=198 mg, 78%; colorless oil; R_(f)=0.15 in 10% EtOAc-hexane;

IR (neat): 3200-3600, 2976, 1747, 1185, 1111, 1024 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz) δ 6.04-6.08 (m, 1H), 5.84-5.89 (m, 1H), 4.25-4.35 (m, 1H), 4.09-4.15 (m, 3H), 3.88 (dd, J=12.8, 2.8 Hz, 1H), 3.40 (dd, J=6.0, 2.8 Hz, 1H), 1.47 (s, 3H), 1.44 (s, 3H);

¹³C NMR (CDCl₃, 100 MHz) δ 132.03 (CH), 123.20 (CH), 98.99 (C), 69.50 (CH), 65.29 (CH₂), 62.99 (CH₂), 61.57 (CH), 28.19 (CH₃), 19.82 (CH₃);

MS (m/z, relative intensity): 170 (M⁺, 5), 169 (55), 97 (91), 83 (54), 70 (100); HRMS calculated for C₉H₁₄O₃ (M⁺): 170.0943; found 170.0939.

Example 51 Preparation of cis-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol

To a solution of cis-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane (50 mg, 0.29 mmol) in MeOH (5 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The mixture was stirred for 30 min at ambient temperature. Aqueous saturated NaHCO₃ (5 mL) was added and the mixture was diluted with EtOAc (50 mL). The organic layer was washed with saturated NaHCO₃ (30 mL). The aqueous layer was washed with EtOAc (30 mL×2). The combined organic layers were dried over Na₂SO₄, concentrated in vacuo, and the residue was purified by flash chromatography with 100% EtOAc

Yield=29 mg, 78% yield; colorless oil; R_(f)=0.25 in EtOAc;

Example 52 Preparation of trans-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol

To a solution of trans-5-allyloxy-2,2-dimethyl-4-vinyl-[1,3]dioxane (48 mg, 0.28 mmol) in MeOH (5 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The mixture was stirred for 30 min at ambient temperature. Aqueous saturated NaHCO₃ (5 mL) was added and the mixture was diluted with EtOAc (50 mL). The organic layer was washed with saturated NaHCO₃ (30 mL). The aqueous layer was washed with EtOAc (30 mL×2). The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated in vacuo, and the residue was purified by flash chromatography with 100% EtOAc.

Yield=30 mg, 83% yield; colorless oil; R_(f)=0.20 in 100% EtOAc;

Example 53 Preparation of trans-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol bis-(S)-Mosher ester

To a solution of (S)-Mosher acid (108 mg, 0.46 mmol) in dry benzene (1 mL) were added sequentially oxalyl chloride (0.5 mL) and DMF (1 drop). The solution was stirred for 5 min at ambient temperature, concentrated in vacuo and diluted with dry CH₂Cl₂(3 mL). Et₃N (0.13 mL, 0.92 mmol), DMAP (11 mg, 0.08 mmol) and a solution of racemic trans-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol (22 mg, 0.17 mmol) in CH₂Cl₂ (2 mL) were added sequentially and the solution was stirred for 24 H. H₂O (2 ml) was added and the mixture was diluted with CH₂Cl₂ (50 mL) and washed with brine (30 mL). The aqueous layer was washed with CH₂Cl₂ (50 mL×2). The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated in vacuo, and the residue was purified by flash chromatography with 10% EtOAc-hexane

Yield=79 mg, 83%; colorless oil; R_(f)=0.69 in 20% EtOAc-hexane.

IR (neat): 2952, 2849, 1752, 1650, 1495, 1271, 1170, 1122, 1023, 765 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz, two isomers): δ 7.45-7.51 (m, 8H), 7.31-7.41 (m, 12H), 6.10-6.15 (m, 2H), 6.07-6.08 (m, 2H), 5.14-5.16 (m, 1H), 5.07-5.09 (m, 1H), 4.52-4.56 (m, 1H), 4.25-4.40 (m, 4H), 4.05-4.18 (m, 3H), 3.89-3.98 (m, 2H), 3.52-3.59 (m, 9H), 3.46-3.47 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz, two isomers): δ 166.64 (C), 166.61 (C), 166.53 (C), 166.41 (C), 134.34 (CH), 134.14 (CH), 132.57 (C), 132.44 (C), 132.34 (C), 132.00 (C), 130.14 (2×CH), 130.10 (four of CH), 129.59 (C), 128.87 (six of CH and 2×C), 128.72 (two C), 127.97 (2×CH), 127.71 (four of CH), 127.68 (two C), 127.57 (2×CH), 126.96 (C), 121.02 (CH), 120.81 (CH), 73.44 (CH), 73.04 (CH), 67.03 (CH), 67.01 (CH), 65.91 (CH₂), 65.86 (CH₂), 64.71 (CH₂), 64.50 (CH₂), 55.86 (2×CH₃), 55.70 (2×CH₃); MS (m/z, relative intensity): 562 (M⁺,2), 342 (10), 128 (23), 91 (100);

Example 54 Preparation of cis-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol bis-(S)-Mosher ester

To a solution of (S)-Mosher acid (108 mg, 0.46 mmol) in dry benzene (1 mL) were added sequentially oxalyl chloride (0.5 mL) and DMF (1 drop). The solution was stirred for 5 min at ambient temperature, concentrated in vacuo and diluted with dry CH₂Cl₂ (3 mL). Et₃N (0.13 mL, 0.92 mmol), DMAP (11 mg, 0.08 mmol), a solution of racemic cis-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol (20 mg, 0.16 mmol) in CH₂Cl₂ (2 mL) were added sequentially and the solution was stirred for 24 H. H₂O (2 ml) was added and the mixture was diluted with CH₂Cl₂ (50 mL) and washed with brine (30 mL). The aqueous layer was washed with CH₂Cl₂ (50 mL×2). The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated in vacuo, and the residue was purified by flash chromatography with 10% EtOAc-hexane

Yield=80 mg, 89%; colorless oil; R_(f)=0.49 in 20% EtOAc-hexane;

IR (neat): 2952, 2850, 1750, 1657, 1452, 1270, 1170, 1122, 1019, 721 cm⁻¹;

¹H NMR (CDCl₃, 400 MHz, two isomers): δ 7.58-7.45 (m, 8H), 7.40-7.30 (m, 12H), 6.00-5.90 (m, 2H), 5.85-5.80 (m, 1H), 5.78-5.70 (m, 1H), 5.48-5.38 (m, 2H), 4.44-4.35 (m, 2H), 4.20-4.03 (m, 6H), 3.82-3.72 (m, 1H), 3.70-3.65 (m, 1H), 3.555-3.45 (s, 12H); ¹³C NMR (CDCl₃, 100 MHz, two isomers): δ 166.35 (C), 166.20 (C), 166.14 (C), 165.81 (C), 132.11 (C), 132.07 (C), 132.01 (C), 131.66 (C), 130.64 (2×CH), 130.61 (2×CH), 129.81 (2×CH), 129.77 (2×CH), 129.65 (2×CH), 129.63 (2×CH), 128.59 (2×CH and one C), 128.53 (2×CH and one C), 128.19 (2×CH and 2×C), 127.41 (2×CH), 127.29 (2×C), 126.97 (2×C), 123.03 (two CH), 122.65 (2×CH), 73.09 (CH), 73.01 (CH), 67.40 (CH), 67.19 (CH), 65.36 (CH₂), 65.01 (CH₂), 64.40 (CH₂), 63.97 (CH₂), 55.48 (2×CH₃), 55.38 (2×CH₃); MS (m/z, relative intensity): 561 (M⁺−1, 5), 345 (9), 128 (22), 105 (52), 95 (70), 91 (100);

Example 55 Preparation of racemic (4aS,7R,8R,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of 2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine (50 mg, 0.29 mmol) in 4.5 mL of THF-tert-BuOH—H₂O (1:3:0.5) was added NMO (45 mg, 0.32 mmol) and the solution was stirred for 5 min at ambient temperature. OsO₄ (15 μL, 25 wt % in tert-BuOH) was added and the solution was stirred at ambient temperature for 4 days. Sodium hydrosulphite (0.2 g), Florisil (2.0 g) and H₂O (5 ml) were added and the mixture was stirred for 30 minutes, wash with acetone (100 mL), filtered through filter paper and extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, concentrated in vacuo, and the residue was purified by flash chromatography with 60% EtOAc-hexane.

Yield=41 mg, 70%; colorless oil; R_(f)=0.13 in 70% EtOAc-hexane;

IR (neat) 3550-3100, 2929, 1392, 1081 cm⁻¹;

¹H NMR (C₆D₆, 400 MHz) δ 4.02-4.12 (m, 1H), 3.90-3.95 (m, 2H), 3.71-3.83 (m, 2H), 3.50-3.60 (m, 2H), 3.26 (br s, 1H), 1.48 (s, 3H), 1.15 (s, 3H);

¹³C NMR (C₆D₆, 100 MHz) δ 99.02 (C), 70.55 (CH), 70.34 (CH), 67.05 (CH), 66.08 (CH₂), 65.61 (CH), 63.83 (CH₂), 30.27 (CH₃), 19.35 (CH₃);

MS (m/z, relative intensity): 204 (M⁺, 5), 170 (18), 146 (12), 103 (42), 91 (91), 43 (100);

HRMS calculated for C₉H₁₆O₅ (M⁺): 204.0998; found 204.0993.

Example 56 Preparation of the bis-(S)-Mosher ester of racemic (4aS,7R,8R,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of (S)-Mosher acid (130 mg, 0.64 mmol) in dry benzene (1 mL) were sequentially added oxalyl chloride (0.5 mL) and DMF (1 drop). The solution was stirred for 5 min at ambient temperature, concentrated in vacuo and diluted with dry CH₂Cl₂ (3 mL). Et₃N (0.45 mL, 3.20 mmol), DMAP (40 mg, 0.32 mmol) and a solution of 2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (130 mg, 0.64 mmol) in CH₂C₆ (2 mL) were added sequentially and the solution was stirred for 24 H. H₂O (2 ml) was added, the mixture was diluted with CH₂Cl₂ (50 mL) and washed with brine (30 mL). The aqueous layer was washed with CH₂Cl₂ (50 mL×2). The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated in vacuo, and the residue was purified by flash chromatography with 5% EtOAc-hexane

Yield=314 mg, 72%; colorless oil; R_(f)=0.68 in 10% EtOAc-hexane; IR (neat): 3100-3650, 2926, 1377, 1321, 1156, 1108, 1062 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz, two isomers) δ 7.55-7.50 (m, 6H), 7.47-7.28 (m, 12H), 7.19-7.15 (m, 2H), 5.57-5.31 (m, 4H), 4.10-3.20 (m, 12H), 3.61 (s, 3H), 3.47 (s, 3H), 3.45 (s, 3H), 3.27 (s, 3H), 1.38 (s, 3H), 1.36 (s, 6H), 1.18 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz, two isomers) δ 166.06 (C), 165.78 (C), 165.34 (C), 165.26 (C), 132.19 (C), 132.12 (C), 131.82 (C), 131.50 (C), 129.61 (CH), 129.52 (2×CH), 129.51 (C), 129.46 (CH), 128.29 (six of CH), 128.22 (3×CH), 128.13 (3×CH), 127.54 (2×C), 127.46 (2×CH), 127.36 (C), 127.09 (2×CH), 124.56 (C), 124.50 (C), 121.69 (C), 121.62 (C), 99.92 (2×C), 73.26 (2×CH), 72.53 (CH), 71.90 (CH), 71.81 (CH), 71.76 (CH), 69.13 (CH), 68.73 (CH), 68.32 (CH₂), 68.05 (CH₂), 61.88 (CH₂), 60.30 (CH₂), 55.55 (CH₃), 55.49 (CH₃), 55.26 (CH₃), 55.03 (CH₃), 28.96 (CH₃), 28.91 (CH₃), 18.77 (CH₃), 18.39 (CH₃); MS (m/z, relative intensity): 636 (M⁺, 2), 417 (3), 376 (15), 283 (39), 189 (100), 105 (22), 95 (51); HRMS calculated for C₂₉H₃₀O₉F₆ (M⁺): 636.1890; found 636.1900.

Example 57 Preparation of the (−)-(4aR,7R,8R,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol and (+)-(4aS,7R,8R,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of racemic trans-2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine (70 mg, 0.41 mmol) in H₂O-tert-BuOH (1:1, 4 mL), were added sequentially K₃Fe(CN)₈ (430 mg, 1.24 mmol), K₂CO₃ (180 mg, 1.24 mmol), MeSO₂NH₂ (75 mg, 0.82 mmol) and (DHQ)₂PHAL (31 mg, 0.04 mmol) at 0° C. The solution was stirred for 5 min, OsO₄ (10 uL, 25 wt % in tert-BuOH) was added and the mixture was stirred for 64 H at ambient temperature. Na₂SO₃ (100 mg) was added and the mixture was stirred for 30 min, filtered through filter paper and extracted with EtOAc—H₂O (4:1 v/v, 100 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, concentrated in vacuo, and the residue was purified by flash chromatography with 100% EtOAc.

(−)-(4aR,7R,8R,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

Yield=21 mg, 25%; colorless oil; R_(f)=0.30 in 100% EtOAc;

IR (neat): 3200-3600, 2976, 1747, 1185, 1111, 1024 cm⁻¹;

¹H NMR (C₆D₆, 500 MHz) δ 3.97 (dd, J=9.5 Hz, 1H), 3.90-3.82 (m, 2H), 3.74 (dd, J=10.5, 10.5 Hz, 1H), 3.56 (brs, 1H), 3.41 (dd, J=9.5, 3.5 Hz, 1H), 3.04-2.98 (m, 2H), 2.84 (br s, 2 OH), 1.45 (s, 3H), 1.27 (s, 3H); ¹³C NMR (C₆D₈, 125 MHz) δ 99.86 (C), 72.69 (CH), 72.15 (CH), 72.02 (CH), 70.36 (CH₂), 69.73 (CH), 62.30 (CH₂), 29.47 (CH₃), 19.12 (CH₃); MS (m/z, relative intensity): 204 (M⁺, 5), 186 (12), 98 (28), 73 (100); exact mass calculated for C₉H₁₆O₅ (M⁺): 204.0998; found 204.0991.

(+)-(4aS,7R,8R,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

Yield=36 mg, 43%; colorless oil; R_(f)=0.51 in 100% EtOAc;

IR (neat): 3200-3600, 2976, 1747, 1185, 1111, 1024 cm⁻¹; ¹H NMR (C₆D₆, 500 MHz) δ 3.88 (dd, J=10.0, 4.5 Hz, 1H), 3.85 (br s, 1H), 3.73 (dd, J=10.5, 5.5 Hz, 1H), 3.60-3.48 (m, 3H), 3.37 (dd, J=10.5, 10.5 Hz, 1H), 3.21 (d, J=10.5 Hz, 1H), 1.36 (s, 3H), 1.15 (3, 3H); ¹³C NMR (CeDe, 125 MHz) δ 99.32 (C), 72.24 (CH), 68.96 (CH), 67.40 (CH), 67.29 (CH₂), 66.62 (CH), 62.87 (CH₂), 29.19 (CH₃), 19.10 (CH₃); MS (m/z, relative intensity): 204 (M⁺, 3), 186 (8), 158 (4), 115 (10), 98 (26), 73 (100); exact mass calculated for C₉H₁₆O₅ (M⁺): 204.0998; found 204.0991.

Example 58 Preparation of (−)-(2R,3S,4R,5R)-2-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To a solution of (−)-(4aR,7R,8R,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (42 mg, 0.21 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.6 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1H at ambient temperature and concentrated in vacuo.

Yield=28 mg, 83% yield;

IR (neat): 3000-4900, 2927, 1421, 1274, 1067 cm⁻¹; ¹H NMR (D₂O, 500 MHz) δ 3.86 (br s, 1H), 3.80 (dd, J=12.5, 1.5 Hz, 1H), 3.77 (dd, J=12.5, 2.5 Hz, 1H), 3.58-3.44 (m, 4H), 3.20-3.16 (m, 1H); ¹³C NMR (D₂O, 125 MHz) a 80.68 (CH), 73.67 (CH), 70.00 (CH₂), 69.24 (CH), 67.45 (CH), 61.40 (CH₂); MS (m/z, relative intensity): 164 (M⁺, 5), 145 (32), 128 (10), 102 (71), 73 (100); exact mass calculated for C₆H₁₂O₆ (M⁺): 164.0685; found 164.0690.

Example 59 Preparation of (−)-(2S,3R,4R,5R)-2-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To a solution of (+)-(4aS,7R,8R,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (28 mg, 0.14 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.4 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1H at ambient temperature and concentrated in vacuo.

Yield=17 mg, 74% yield;

IR (neat): 3000-3600, 2938, 1418, 1231, 1057, 911, 773 cm⁻¹;

¹H NMR (D₂O, 500 MHz) δ 4.04 (br s, 1H), 3.75 (d, J=12.0 Hz, 1H), 3.71-3.66 (m, 1H), 3.65-3.60 (m, 1H), 3.57-3.52 (m, 1H), 3.46-3.38 (m, 3H);

¹³C NMR (D₂O, 125 MHz) δ 75.07 (CH), 70.56 (CH), 67.07 (CH), 66.78 (CH), 64.48 (CH₂), 61.34 (CH₂);

MS (m/z, relative intensity): 164 (M⁺, 4), 146 (13), 128 (10), 103 (40), 102 (52), 98 (32), 73 (100); exact mass calculated for C₆H₁₂O₅ (M⁺): 164.0685; found 164.0688.

Example 60 Preparation of (+)-(4aS,7R,8R,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of racemic cis-2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine (100 mg. 0.58 mmol) in 4 mL of H₂O-tert-BuOH (1:1), were added sequentially K₃Fe(CN)₆ (580 mg, 1.76 mmol), K₂CO₃ (243 mg, 1.76 mmol), MeSO₂NH₂ (110 mg, 1.16 mmol) and (DHQD)₂PHAL (60 mg, 0.08 mmol) at 0° C. The solution was stirred for 5 min and OsO₄ (10 μL, 25 wt % in tert-BuOH) was added and stirring was maintained for 62 H at ambient temperature. Na₂SO₃ (100 mg) was added and the mixture was stirred for 30 min, filtered through filter paper and extracted with EtOAc—H₂O (4:1 v/v, 100 mL×2). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash chromatography with 100% EtOAc.

Yield=72 mg, 61%; colorless oil; R_(f)=0.35 in 100% EtOAc;

IR (neat) 3600-3100, 2987, 2920, 1382, 1086 cm⁻¹; ¹H NMR (C₆D₆, 400 MHz) δ 4.02-3.95 (m, 1H), 3.90-3.82 (m, 3H), 3.63 (dd, J=10.6, 5.4 Hz, 1H), 3.54 (dd, 12.7, 2.2 Hz, 1H), 3.47 (dd, J=10.6, 10.6 Hz, 1H), 3.18 (br s, 1H), 1.47 (s, 3H), 1.14 (s, 3H); ¹³C NMR (C₆D₆, 100 MHz) δ 98.29 (C), 69.70 (CH), 69.56 (CH), 66.30 (CH), 65.21 (CH₂), 64.80 (CH), 63.08 (CH₂), 29.57 (CH₃), 18.62 (CH₃); MS (m/z, relative intensity): 204 (M⁺, 5), 170 (18), 146 (12), 103 (42), 91 (91), 59 (40), 57 (40), 43 (100); exact mass calculated for C₉H₁₆O₅ (M⁺): 204.0998; found 204.0993.

Example 61 Preparation of (+)-(2S,3S,4R,5R)-2-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To a solution of (+)-(4aS,7R,8R,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (36 mg, 0.18 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1 H at ambient temperature and concentrated in vacuo.

Yield=15 mg, 76%;

IR (neat): 3000-3600, 2944, 2913, 2891, 1460, 1380, 1296, 1114, 1024 cm⁻¹; ¹H NMR (D₂O, 400 MHz) δ 4.00-3.90 (m, 2H), 3.76-3.73 (m, 1H), 3.72-3.65 (m, 2H), 3.62-3.60 (m, 2H), 3.45 (dd, J=10.6 Hz, 1H); ¹³C NMR (D₂O, 100 MHz) 875.34 (CH), 69.86 (CH), 69.72 (CH), 65.36 (CH₂), 64.57 (CH), 61.40 (CH₂); MS (m/z, relative intensity): 164 (M⁺, 2), 146 (13), 128 (11), 103 (33), 102 (26), 74 (31), 73 (72), 70 (100); exact mass calculated for C₆H₁₂O₅ (M⁺): 164.0685; found 164.0680.

Example 62 Preparation of (+)-(4aS,7S,8S,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol and (−)-(4aR,7S,8S,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of racemic trans-2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine (75 mg, 0.44 mmol) in 4 mL of H₂O-tert-BuOH (1:1), were added sequentially K₃Fe(CN)₆ (435 mg, 1.32 mmol), K₂CO₃ (182 mg, 1.32 mmol), MeSO₂NH₂ (76 mg, 0.88 mmol) and (DHQD)₂PHAL (31 mg, 0.04 mmol) at 0° C. The solution was stirred for 5 min, OsO₄ (10 μL, 25% wt in tert-BuOH) was added and the mixture was stirred for 56 H at ambient temperature. Na₂SO₃ (100 mg) was added and the mixture was stirred for 30 min, filtered through filter paper and extracted with EtOAc—H₂O (4:1 v/v, 100 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, concentrated in vacuo and the residue was purified by flash chromatography with 100% EtOAc.

(+)-(4aS,7S,8S,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

Yield=27 mg, 30%; colorless oil; R_(f)=0.29 in 100% EtOAc;

IR (neat): 3150-3600, 2965, 1749, 1901, 1124, 1096 cm⁻¹; ¹H NMR (C₆D₆, 500 MHz) δ 4.02 (dd, J=9.5, 9.5 Hz, 1H), 3.90-3.86 (m, 2H), 3.77 (dd, J=10.5, 10.5 Hz, 1H), 3.62 (br s, 1H), 3.46 (dd, J=9.5, 3.0 Hz, 1H), 3.19 (br. s, 2H), 3.20-3.00 (m, 2H), 1.47 (s, 3H), 1.31 (s, 3H); ° C. NMR (C₆D₆, 125 MHz) δ 99.92 (C), 72.77 (CH), 72.13 (CH), 72.02 (CH), 70.47(CH₂), 69.82 (CH), 62.28 (CH₂), 29.48 (CH₃), 19.15 (CH₃); MS (m/z, relative intensity): 204 (M⁺, 1), 186 (19), 170 (17), 128 (34), 105 (39), 97 (91), 84 (100); exact mass calculated for C₉H₁₆O₅ (M⁺): 204.0998; found 204.0999.

(−)-(4aR,7S,8S,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

Yield=39 mg, 43%; colorless oil; R_(f)=0.41 in 100% EtOAc;

IR (neat): 3200-3600, 2976, 1747, 1185, 1111, 1024 cm⁻¹; ¹H NMR (C₆D₆, 500 MHz) δ 3.88 (dd, J=11.5, 4.5 Hz, 1H), 3.85 (brs, 1H), 3.74 (dd, J=11.0, 6.0 Hz, 1H), 3.60-3.50 (m, 3H), 3.72 (dd, J=11.0, 11.0 Hz, 1H), 3.21 (dd, J=9.0, 2.0 Hz, 1H), 1.37 (s, 3H), 1.15 (s, 3H); ¹³C NMR (C₆D₆, 125 MHz) δ 99.32 (C), 72.24 (CH), 68.96 (CH), 67.40 (CH), 67.29 (CH₂), 66.62 (CH), 62.87 (CH₂), 29.20 (CH₃), 19.09 (CH₃); MS (m/z, relative intensity): 186 (M⁺−18, 5), 170 (6), 128 (39), 105 (42), 97 (91), 84 (100); exact mass calculated for C₉H₁₆O₅ (M⁺): 204.0998; found 204.0989

Example 63 Preparation of (+)-(2S,3R,4S,5S)-2-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To a solution of (+)-(4aS,7S,8S,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (24 mg, 0.12 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.4 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1 H at ambient temperature and concentrated in vacuo.

Yield=17 mg, 85%; IR (neat): 3000-4900, 2927, 1421, 1274, 1067 cm⁻¹; ¹H NMR (D₂O, 500 MHz) δ 3.86 (br s, 1H), 3.81 (dd, J=12.5, 1.5 Hz, 1H), 3.78 (dd, J=12.5, 2.5 Hz, 1H), 3.57 (dd, J=12.5, 6.5 Hz, 1H), 3.55-3.49 (m, 2H), 3.46 (d, J=9.5 Hz, 1H), 3.18 (ddd, J=9.5, 6.5, 2.5 Hz, 1H); ¹³C NMR (H₂O₁ 125 MHz) δ 80.67 (CH), 73.99 (CH), 69.99 (CH₂), 69.22 (CH), 67.45 (CH), 61.39 (CH₂); MS (m/z, relative intensity): 164 (M⁺, 3), 146 (12), 128 (7), 102 (34), 98 (16), 73 (100); exact mass calculated for C₆H₁₂O₅ (M⁺): 164.0685; found 164.0692.

Example 64 Preparation of (+)-(2R,3S,4S,5S)-2-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To a solution of (−)-(4aR,7S,8S,8aS)-2,2-dimethyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (20 mg, 0.09 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1H at ambient temperature and concentrated in vacuo.

Yield=12 mg, 74%;

IR (neat): 3000-3600, 2938, 1418, 1231, 1057, 911, 773 cm⁻¹; ¹H NMR (D₂O, 500 MHz) δ 4.03 (br s, 1H), 3.74 (dd, J=12.0, 1.2 Hz, 1H), 3.69-3.64 (m, 1H), 3.61 (dd, J=10.5, 5.5 Hz, 1H), 3.56-3.50 (m, 1H), 3.45-3.43 (m, 2H), 3.40 (dd, J=10.5, 10.5 Hz, 1H); ¹³C NMR (D₂O, 125 MHz) δ 75.03 (CH), 70.55 (CH), 67.03 (CH), 66.75 (CH), 64.46 (CH₂), 61.31 (CH₂); MS (m/z, relative intensity): 164 (M⁺, 5), 146 (13), 128 (9), 103 (38), 102 (50), 73 (100); exact mass calculated for C₆H₁₂O₅ (M⁺): 164.0685; found 164.0685.

Example 65 Preparation of (−)-(4aR,7S,8S,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of racemic cis-2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine (52 mg. 0.30 mmol) in 4 mL of H₂O-tert-BuOH (1:1), were added sequentially K₃Fe(CN)₆ (312 mg, 0.90 mmol), K₂CO₃ (131 mg, 0.90 mmol), MeSO₂NH₂ (55 mg, 0.60 mmol) and (DHQ)₂PHAL (23 mg, 0.03 mmol) at 0° C. The mixture was stirred for 5 min., OsO₄ (10 μL, 25 wt % in tert-BuOH) was added and the mixture was stirred for 64 H at ambient temperature. Na₂SO₃ (100 mg) was added and the mixture was stirred for 30 min, filtered through filter paper and extracted with EtOAc—H₂O (4:1 v/v, 100 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography with 100% EtOAc.

Yield=22 mg, 36%; colorless oil; R_(f)=0.46 in EtOAc;

IR (neat): 3200-3600, 2976, 1747, 1185, 1111, 1024 cm⁻¹;

¹H NMR (C₆D₆, 400 MHz) δ 4.00-3.95 (m, 1H), 3.90-3.80 (m, 3H), 3.63 (dd, J=10.6, 5.5 Hz, 1H), 3.56 (d, J=2.0 Hz, 1H), 3.53-3.47 (m, 1H), 3.18 (brs, 1H), 1.47 (s, 3H), 1.14 (s, 3H);

¹³C NMR (C₆D₆, 100 MHz) δ 98.28 (C), 69.70 (CH), 69.56 (CH), 66.31 (CH), 65.21 (CH₂), 64.80 (CH), 63.08 (CH₂), 29.57 (CH₃), 18.62 (CH₃);

MS (m/z, relative intensity): 204 (M⁺, 6), 170 (19), 146 (12), 103 (42), 91 (92), 43 (100);

HRMS calculated for C₉H₁₆O₅ (M⁺): 204.0998; found 204.0989.

Example 66 Preparation of (−)-(2R,3R,4S,5S)-2-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To a solution of (−)-(4aR,7S,8S,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (22 mg, 0.10 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1H at ambient temperature. Aqueous saturated NaHCO₃ (5 mL) was added and the mixture was diluted with EtOAc (50 mL). The mixture was washed with saturated NaHCO₃ (30 mL). The aqueous layer was washed with EtOAc (30 mL×2). The combined organic layers were dried over Na₂SO₄, and concentrated in vacuo

Yield=13 mg, 82%;

IR (neat): 3000-3600, 2944, 2913, 2891, 1460, 1380, 1296, 1114, 1024 cm⁻¹; ¹H NMR (D₂O, 500 MHz) δ 3.92-3.83 (m, 2H), 3.72-3.70 (m, 1H), 3.69-3.60 (m, 2H), 3.58-3.55 (m, 2H), 3.42 (dd, J=10.5, 10.5 Hz, 1H); ¹³C NMR (D₂O, 125 MHz) δ 77.67 (CH), 72.15 (CH), 72.03 (CH), 67.67 (CH₂), 66.86 (CH), 63.73 (CH₂); MS (m/z, relative intensity): 164 (M⁺, 2), 146 (13), 128 (9), 103 (33), 102 (26), 74 (33), 73 (81), 43 (100); exact mass calculated for C₆H₁₂O₅ (M⁺): 164.0685; found in 164.0689.

Example 67 Preparation of (+)-(4aS,7S,8S,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of optically pure (4aS,8aR-2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine (50 mg, 0.29 mmol) in 4.5 mL of THF-tert-BuOH-H₂O (1:3:0.5) was added NMO (45 mg, 0.32 mmol) and the solution was stirred for 5 min. at ambient temperature. OsO₄ (15 μL, 25 wt % In tert-BuOH) was added and the solution was stirred at ambient temperature for 4 days. Sodium hydrosulphite (0.2 g), Florisil (2.0 g) and H₂O (5 ml) were added and the mixture was stirred for 30 min, wash with acetone (100 mL), filtered through filter paper and extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography with 100% EtOAc.

Yield=44 mg, 74%; optical purity=99.0%;

Example 68 Preparation of (+)-(4aR,7S,8S,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of optically pure (4aR,8aS-2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine (50 mg, 0.29 mmol) in 4.5 mL of THF-tert-BuOH—H₂O (1:3:0.5) was added NMO (45 mg, 0.32 mmol) and the solution was stirred for 5 min. at ambient temperature. OsO₄ (15 μL, 25 wt % in tert-BuOH) was added and the solution was stirred at ambient temperature for 4 days. Sodiumhydrosulphite (0.2 g), Florisil (2.0 g) and H₂O (5 ml) were added and the mixture was stirred for 30 min, wash with acetone (100 mL), filtered through filter paper and extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography with 100% EtOAc.

Yield=42 mg, 71%; optical purity=99%

Example 69 Preparation of (+)-(4aS,7R,8R,8aS)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of optically pure (4aS,8aS)-2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine (48 mg, 0.28 mmol) in 4.5 mL of THF-tert-BuOH—H₂O (1:3:0.5) was added NMO (45 mg, 0.32 mmol) and the solution was stirred for 5 min. at ambient temperature. OsO₄ (15 μL, 25 wt % in tert-BuOH) was added and the solution was stirred at ambient temperature for 4 days. Sodiumhydrosulphite (0.2 g), Florisil (2.0 g) and H₂O (5 ml) were added and the mixture was stirred for 30 min, wash with acetone (100 mL), filtered through filter paper and extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography with 100% EtOAc.

Yield=43 mg, 76%; optical purity=99%

Example 70 Preparation of (−)-(4aR,7S,8S,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of optically pure (4aR,8aR)-2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine (50 mg, 0.29 mmol) in 4.5 mL of THF-tert-BuOH—H₂O (1:3:0.5) was added NMO (45 mg, 0.32 mmol) and the solution was stirred for 5 min. at ambient temperature. OsO₄ (15 μL, 25 wt % in tert-BuOH) was added and the solution was stirred at ambient temperature for 4 days. Sodiumhydrosulphite (0.2 g), Florisil (2.0 g) and H₂O (5 ml) were added and the mixture was stirred for 30 min, wash with acetone (100 mL), filtered through filter paper and extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography with 100% EtOAc.

Yield=37 mg, 63%; optical purity=99%

Example 71 Preparation of 2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol

To a solution of 2,2-dimethyl-4,4a,6,8a-tetrahydro-pyrano[3,2-d][1,3]dioxine (50 mg, 0.29 mmol) in 4.5 mL of THF-tert-BuOH—H₂O (1:3:0.5) was added NMO (45 mg, 0.32 mmol) and the solution was stirred for 5 min. at ambient temperature. OsO₄ (15 μL, 25 wt % in tert-BuOH) was added and the solution was stirred at ambient temperature for 4 days. Sodiumhydrosulphite (0.2 g), Florisil (2.0 g) and H₂O (5 ml) were added and the mixture was stirred for 30 min, wash with acetone (100 mL), filtered through filter paper and extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography with 100% EtOAc.

Yield=41 mg, 70%.

IR (neat): 3000-3600, 2952, 1473, 1268, 1161, 1087, 1021 cm⁻¹;

¹H NMR (C₈D₆, 400 MHz) δ 3.80-4.00 (m, 3H), 3.75 (dd, J=13.2, 13.2 Hz, 1H), 3.53 (br s, 1H), 3.35-3.42 (m, 1H), 2.90-3.00 (m, 2H), 2.50 (br s, 1H), 1.44 (s, 3H), 1.24 (s, 3H);

¹³C NMR (C₆D₆, 100 MHz) δ 99.86 (C), 72.65 (CH), 72.14 (CH), 72.03 (CH), 70.29 (CH₂), 69.68 (CH), 62.30 (CH₂), 29.47 (CH₃), 19.12 (CH₃); MS (m/z, relative intensity): 186 (M⁺−18, 6), 170 (7), 141 (3), 128 (36), 115 (42), 95 (91), 84 (100).

Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims. 

1. A process for preparing compound of formula H comprising contacting compound of formula G under conditions suitable to produce compound of formula H,

wherein: a) R₁ is selected from the group consisting of alkyl, substituted alkyl and aryl; b) R₂ and R₅ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl and aryl; c) R₃=R₄=R₆=R₇=hydrogen, or R₃, R₄, R₆, R₇ are selected such that three out of four are hydrogen and the fourth is selected from the group consisting of alkyl, substituted alkyl and aryl; and d) R₉ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and hydroxyl protecting group.
 2. A process according to claim 1, wherein carboxylic ester of formula G is contacted with a ring-closing metathesis catalyst selected from the group consisting of 2,6-diisopropylphenylimidoneophylidene molybdenum (IV) bis-(tert-butoxide), 2,6-diisopropylphenylimidoneophylidene molybdenum (IV) bis-(hexafluoro-tert-butoxide), 2,6-diisopropylphenylimidoneophylidene[racemic-BIPHEN]molybdenum (IV), 2,6-diisopropylphenylimidoneophylidene[(R)-(+)-BIPHEN]molybdenum (IV), 2,6-diisopropylphenylimidoneophylidene[(S)-(−)-BIPHEN]molybdenum (IV), bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, bis-(tricyclohexylphosphine)-3-methyl-2-butenylidene ruthenium (IV) dichloride, bis-(tricyclopentylphosphine)benzylidine ruthenium (IV) dichloride, bis-(tricyclopentylphosphine)-3-methyl-2-butenylidene ruthenium (IV) dichloride, tricyclohexylphosphine-(1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)-benzylidine ruthenium (IV) dichloride, tricyclohexylphosphine-(1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene)-benzylidine ruthenium (IV) dichloride, (1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)-2-isopropoxyphenylmethylene ruthenium (IV) dichloride, (tricyclopentylphosphine)-2-isopropoxyphenylmethylene ruthenium (IV) dichloride, and (tricyclopentylphosphine)-2-methoxy-3-naphthylmethylene ruthenium (IV) dichloride under conditions suitable to produce compound of formula H.
 3. A process according to claim 1, wherein R₁=ethyl, and R₂=R₃=R₄=R₅=R₆=R₇=R₉=hydrogen, or R₁=ethyl, and R₆=methyl, and R₂=R₃=R₄=R₅=R₇=R₉=hydrogen, or R₁=ethyl, and R₆=phenyl, and R₂=R₃=R₄=R₅=R₇=R₉=hydrogen.
 4. A compounds of formula H,

wherein: a) R₁ is selected from the group consisting of alkyl, substituted alkyl and aryl; b) R₂ and R₅ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl and aryl; and c) R₉ is selected from the group consisting of hydrogen, alkylcarbonyl, substituted alkylcarbonyl, arylcarbonyl and hydroxyl protecting group.
 5. The compound of claim 4, wherein the compound includes all stereoisomers of a compound of formula H, wherein R₁=ethyl and R₂=R₅=R₉=hydrogen, or R₁=ethyl and R₂=R₅=hydrogen and R₉=acetyl, including (2R,3R)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2S,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2S,3R)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2R,3S)-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2R,3R)-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2S,3S)-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2R,3S)-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2S,3R)-3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester.
 6. A process for preparing compound of formula H comprising contacting compound of formula I with a resolving enzyme and an acylating agent under suitable conditions to produce optically pure 3,6-dihydro-2H-pyran of formula H,

wherein: a) R₁ is selected from the group consisting of alkyl, substituted alkyl and aryl; b) R₂ and R₅ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl and aryl; and c) R₉ is selected from the group consisting of hydrogen, alkylcarbonyl, substituted alkylcarbonyl and arylcarbonyl.
 7. A The process according to claim 6, wherein the enzymatic resolution comprises an enzyme-catalyzed transesterification of a compound of formula I, wherein the enzymatic resolution includes the use of a lipase, esterase, peptidase, acylase or protease enzyme of mammalian, plant, fungal or bacterial origin is selected from the group consisting of Lipase Amano lipase PS-D (immobilized lipase from Pseudomonas cepacia), Amano Lipase PS-C (immobilized lipase from Pseudomonas cepacia), Roche Chirazyme L-3 (lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, lyophilizate, from Candida Rugosa), Roche Chirazyme L-3 (purified lipase, carrier-fixed, carrier 2, lyophilizate, from Candida rugosa), Roche Chirazyme L-5 (lipase, solution, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, lyophilizate, from Candida antartica, type A), Roche Chirazyme L-5 (lipase, carrier-fixed, carrier 1, lyophilizate, from Candida antartica, type A), Roche Chirazyme L-10 (lipase, lyophilizate, from Alcaligines sp.), Altus Biologics 8 (lipase from Mucor meihei) and Altus Biologics 27 (lipase from Alcaligenes sp.), and wherein the acylating agent is selected from the group consisting of ethyl acetate, vinyl acetate, vinyl propionate, vinyl butyrate, isopropenyl acetate, 1-ethoxyvinyl acetate, trichloroethyl butyrate, trifluoroethyl butyrate, trifluoroethyl laureate, S-ethyl thiooctanoate, biacetyl monooxime acetate, acetic anhydride, succinic anhydride, amino acid and diketene, and where the reaction is carried out between 0° C. and 40° C. in a solvent or in mixtures of solvents selected from the group consisting of acetonitrile, dichloromethane, dichloroethane, diethyl ether, dioxane, tetrahydrofuran, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide, benzene, toluene, dichlorobenzene, xylene, methanol, ethanol, isopropanol and water and wherein the optically pure 3,6-dihydro-2H-pyran H is isolated by the use of at least one method selected from the group consisting of chromatography, crystallization, re-crystallization and distillation.
 8. The process according to claim 6, wherein R₁ is ethyl, R₂ and R₅ are hydrogen, and R₉ is selected from the group consisting of hydrogen and acetyl, and wherein the substituted 3,6-dihydro-2H-pyran H selected from the group consisting of (2R,3R) 3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2S,3S) 3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, (2S,3R) 3-acetoxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester, and (2R,3S) 3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester.
 9. A process for preparing compound of formula J, comprising contacting compound of formula H under conditions suitable to produce a substituted tetrahydropyran of formula J,

wherein: a) R₁ is selected from the group consisting of alkyl, substituted alkyl and aryl; b) R₂ and R₅ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl and aryl; and c) R₉ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylcarbonyl and hydroxyl protecting group.
 10. The process according to claim 9, wherein the compound of formula H is contacted with any suitable mixtures of compounds selected from the group consisting of osmium tetroxide, potassium permanganate, thallium acetate, potassium periodate, silver acetate, N-methylmorpholine oxide, trimethylamine oxide, tert-butyl peroxide, iodine, potassium ferricyanide, pyridine, quinuclidine, dihydroquinine acetate, dihydroquinidine acetate, dihydroquinine anthraquinone-1,4-diyl diether ((DHQ)₂AQN), dihydroquinine phthalazine-1,4-diyl diether ((DHQ)₂PHAL), dihydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)₂PYR), dihydroquinidine anthraquinone-1,4-diyl diether ((DHQD)₂AQN), dihydroquinidine phthalazine-1,4-diyl diether ((DHQD)₂PHAL), dihydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQD)₂PYR), tetraethyl ammonium hydroxide, tetraethyl ammonium acetate, and N,N,N′N′-tetramethylethylene diamine under conditions suitable to produce compound of formula J.
 11. The process according to claim 9, wherein R₁=ethyl, and R₂=R₅=hydrogen and R₉=acetyl, or R₁=ethyl, and R₂=R₅=R₉=hydrogen. 